JP2002275092A - Method for treating obesity with neurotensin receptor ligand - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for treating obesity with a neurotensin receptor ligand, and to obtain a medicine composition therefor. SOLUTION: This method for treating obesity, diabetes, sexual function disorders, atherosclerosis, insulin resistance, glucose tolerance decrease, hypercholesteremia or hypertriglyceridemia uses the neurotensin receptor ligand. A medicinal composition and a kid each contains the neurotensin receptor ligand.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the use of a compound that is a neurotensin receptor ligand for obesity, diabetes, sexual dysfunction (including erectile dysfunction), atherosclerosis, insulin resistance, A method for treating impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia. The present invention also relates to compositions and kits comprising the neurotensin receptor ligand.

[0002]

BACKGROUND OF THE INVENTION Obesity is a catastrophic disease. Obesity is a mental health condition because obesity affects self-esteem that, in addition to impairing physical health, can ultimately affect an individual's ability to interact socially with others. It can bring devastation to the condition. Unfortunately, obesity is not well understood, and social stereotypes and speculation about obesity only tend to exacerbate the psychological effects of obesity. Because of the impact on individuals and society of obesity, much effort has been made to find ways to treat obesity, but long-term treatment and / or prevention of obesity has been largely unsuccessful.

[0003] Neurotensin is a 13-amino acid peptide that is thought to have functions as a neurotransmitter and neuromodulator in the nervous system and as a peripheral local hormone. Specifically, neurotensin is a neuromodulator of dopamine transmission and anterior pituitary hormone secretion, and has potent hypothermic and analgesic effects in the brain. In the periphery, neurotensin is a gastrointestinal paracrine and endocrine modulator;
Acts as a growth factor on various cells.

[0004] So far, three types of neurotensin receptors, namely neurotensin-1 receptor,
Neurotensin-2 receptor and neurotensin-
Three receptors have been identified. (Neurotensin-3 receptor is also referred to as saltrin or gp95.) The receptors for neurotensin-1 and neurotensin-2 are G protein-coupled receptors, whereas neurotensin-3 receptors are Not a protein-coupled receptor.

[0005]

SUMMARY OF THE INVENTION The present invention is a method for treating obesity,
Administering a therapeutically effective amount of a compound that is a neurotensin receptor ligand to an obese patient or a patient at risk of becoming obese.

In a preferred embodiment of these methods,
Neurotensin receptor ligand is neurotensin-
One receptor ligand. In another preferred embodiment of the methods, the neurotensin receptor ligand is a neurotensin-2 receptor ligand.

[0007] In another preferred embodiment of these methods, the neurotensin receptor ligand is a neurotensin-3 receptor ligand. In another preferred embodiment of the methods, the ligand is an agonist.

[0008] In another preferred embodiment of the methods, the ligand is an antagonist. In another preferred embodiment of the methods, the neurotensin receptor ligand is a neurotensin-1 receptor agonist.

[0009] Further provided is a method of treating obesity, wherein a therapeutically effective amount of a compound that is a selective neurotensin-1 receptor agonist is administered to an obese patient or a patient at risk of becoming obese. Is administered.

Also provided is a pharmaceutical composition, comprising: (a) a compound that is a neurotensin receptor ligand;
And (b) a pharmaceutical composition comprising a second compound useful for treating obesity, diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia. is there.

In a preferred embodiment of these compositions, the neurotensin receptor ligand is a neurotensin-1 receptor agonist. In another preferred embodiment of the method, the second compound is a β ₃ adrenergic receptor agonist, a cholecystokinin A agonist, a monoamine reuptake inhibitor, a sympathomimetic, a serotonin agonist, a dopamine agonist, a melanin Cell stimulating hormone receptor agonist or mimic, melanocyte stimulating hormone receptor analog, cannabinoid receptor antagonist, melanin concentrating hormone antagonist, leptin, leptin analog, leptin receptor agonist, galanin antagonist, bombesin agonist, neuropeptide Y antagonist , Thyroid-like substances,
Dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonist or antagonist, orexin receptor antagonist, urocortin binding protein antagonist, glucagon-like peptide
1 receptor agonist, or ciliary neurotrophic factor.

Also provided is a kit, comprising: (a) a first pharmaceutical composition comprising a compound that is a neurotensin receptor ligand; (b) obesity, diabetes, sexual dysfunction, atherosclerosis. A second pharmaceutical composition comprising a compound useful for the treatment of diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia; and (c) a container for the first and second compositions It is a kit containing.

In preferred embodiments of these kits
Neurotensin receptor ligands
-1 receptor agonist. Another of those kits
In one preferred embodiment, the second pharmaceutical composition comprises β
_ThreeAdrenergic receptor agonist, cholecystokine
Nin A agonist, monoamine reuptake inhibitor, sympathetic deity
Agonists, serotonin agonists, dopamine agonists,
Lanin stimulating hormone receptor agonist or mimic
Body, melanocyte stimulating hormone receptor analog, cannabino
Id receptor antagonist, melanin-concentrating hormone an
Tagonist, leptin, leptin analog, leptin receptor
Body agonist, galanin antagonist, bombesinia
Gonist, neuropeptide Y antagonist, thyroid-like
Substance, dehydroepiandrosterone or similar
Body, glucocorticoid receptor agonist or anta
Gonist, orexin receptor antagonist, urocor
Glucagon-like pep, a tin-binding protein antagonist
Tide-1 receptor agonist or ciliary neurotrophic factor
It is.

Further provided is a method of treating diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia, comprising the steps of: Administering a therapeutically effective amount of a neurotensin receptor ligand to a patient with or at risk for dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia. It is a method including.

In a preferred embodiment of the method, the neurotensin receptor ligand is neurotensin-1
Is a receptor ligand. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of a compound that is a neurotensin receptor ligand for obesity, diabetes, sexual dysfunction (including erectile dysfunction), atherosclerosis, insulin resistance, glucose A method for treating impaired tolerance, hypercholesterolemia or hypertriglyceridemia. Further, the present invention provides pharmaceutical compositions and kits comprising a neurotensin receptor ligand.

According to the present invention, obesity, diabetes, sexual dysfunction (including erectile dysfunction), atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia , Obese patients or patients at risk for obesity, or diabetes,
A therapeutically effective dose for patients with sexual dysfunction (including erectile dysfunction), atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia, or at risk for them. It can be treated by administering a neurotensin receptor ligand. In a preferred embodiment of the invention, the neurotensin receptor ligand is a neurotensin-1 receptor ligand. In a more preferred embodiment of the invention, the neurotensin receptor ligand is a selective neurotensin-1 receptor agonist.

The term "therapeutically effective amount" refers to treating a disease; ameliorating, alleviating or eliminating one or more symptoms of a particular disease; An amount of a compound or combination of compounds that prevents or delays initiation is meant.

The term "patient" means animals such as dogs, cats, cows, horses, sheep, cancer and humans. Particularly preferred patients are mammals, including humans of both sexes.

The term "pharmaceutically acceptable" means that the substance or composition should be compatible with the other ingredients of the formulation and must not be harmful to the patient. The terms "treating", "treat" or "treatment" include preventative (eg, prophylactic) and palliative treatment.

The phrase "neurotensin receptor ligand" refers to a compound that binds to a neurotensin receptor, a stereoisomer of the compound, a pharmaceutically acceptable salt of the compound or a stereoisomer, the compound or a stereoisomer. A prodrug of the body or a pharmaceutically acceptable salt of the prodrug. Any additional pharmaceutically active compound used in combination with the neurotensin receptor ligand can be a stereoisomer of the additional active compound, a salt of the additional active compound or a stereoisomer thereof, the additional compound or It is also contemplated that the stereoisomer may be a prodrug, or a salt of the prodrug.

The phrase "neurotensin receptor agonist" refers to a neurotensin receptor ligand that activates a neurotensin receptor. The phrase "neurotensin receptor antagonist" refers to a neurotensin receptor ligand that blocks activation of the neurotensin receptor.

The term "selective" means that one ligand binds to a particular receptor with a greater affinity when compared to the binding affinity of that ligand for another receptor. . Preferably, the binding affinity of the ligand for the first receptor is about 5 to less than the binding affinity for the second receptor.
0% or more. More preferably, the binding affinity of the ligand for the first receptor is about 75% or greater than the binding affinity for the second receptor. Most preferably, the binding affinity of the ligand for the first receptor is about 90% or greater than the binding affinity for the second receptor.
In a preferred embodiment of the invention, the ligand exhibits a greater binding affinity for one of the three neurotensin receptors. Particularly preferred ligands are those that bind to the neurotensin-1 receptor with greater binding affinity when compared to the binding of neurotensin-2 or neurotensin-3 to the receptor. It is believed that preferred compounds bind the neurotensin receptor with micromolar or greater affinity. More preferred compounds bind the neurotensin receptor with nanomolar or greater affinity. Preferred neurotensin receptor ligands of the present invention include compounds that are selective agonists of the neurotensin-1 receptor.

[0023] Neurotensin receptor ligands can be identified, for example, by screening compound libraries. Methods for identifying receptor agonists and antagonists are well known to those skilled in the art. Specific procedures that can be used to identify neurotensin receptor ligands are set forth below.

Examples of known neurotensin receptor ligands include hormones such as neurotensin (also called NT (1-13)) and neuromedin N; US Pat. No. 5,407,916. Such non-peptide agonists; 2-([1- {7-chloro-4-quinolinyl} -5- {2,6-dimethoxyphenyl} pyrazol-3-yl] carboxyl, which is a selective neurotensin-1 receptor antagonist Amino) trichloro (3.3.1.1. [3.7) decane-2-carboxylic acid (SR48692) and non-selective binding with equal affinity at neurotensin-1 and neurotensin-2 receptors The antagonist 2- (5,6
-Dimethylaminopropyl) -1- [4- {N- (3-
Dimethylaminopropyl) -N-methylcarbamoyl
-2-isopropylphenyl] -1H-pyrazole-3
Non-peptide antagonists such as -carbonyl) aminoadamantane-2-carboxylic acid (SR142948A) are included. Another compound that is a neurotensin binding ligand is levocabastin
e). In addition, U.S. Patent Nos. 5,250,558 and 5,204,354 disclose neurotensin receptor antagonists, and
No. 7,916 discloses a neurotensin agonist of a peptide. Examples of selective neurotensin-1 receptor agonists include natural neurotensin [NT (1- (n ₎ with a Kd of about 0.3 nM at the neurotensin-1 receptor and about 2-6 nM at the neurotensin-2 receptor. 13)]. Another example of a selective neurotensin-1 receptor agonist is Trp11 NT (1-13), which exhibits a binding affinity of about 1 nM at the neurotensin-1 receptor and about 27 nM at the neurotensin-2 receptor. . Trp11
NT (1-13) is NT (1-13) where amino acid 11 is tryptophan.

The amino acid and nucleotide sequences encoding each of the three human neurotensin receptors are well known to those skilled in the art and have accession numbers NM-002531, Y10148 and NM-00 in GenBank.
2569.

The neurotensin receptor ligand is administered to a patient in a therapeutically effective amount. The neurotensin receptor ligand can be administered alone or as part of a pharmaceutically acceptable composition. Further, the compound or composition can be administered all at once, e.g., by bolus injection, multiple times, e.g., in a series of tablets, or substantially over a period of time, e.g., using a transdermal delivery system. Can be uniformly supplied. It is also noted that the dose of the compound may vary over time. The neurotensin receptor ligand can be administered using an immediate release formulation, a controlled release formulation, or a combination thereof. The term "controlled release" includes sustained release, delayed release and combinations thereof.

Furthermore, the neurotensin receptor ligand can be administered alone, in combination with other neurotensin receptor ligands, or together with other pharmaceutically active compounds. Other pharmaceutically active compounds may be for treating the same or another disorder as for neurotensin receptor ligands. Patient
If multiple pharmaceutically active compounds are to be or are to be provided, they can be administered simultaneously or sequentially in any order. For example, in the case of tablets, the active compounds may be in one tablet or in separate tablets, which can be administered once or sequentially in any order. Further, it should be understood that the compositions can be in different forms. For example, one or more compounds may be supplied as tablets, while others may be administered orally by injection or as a syrup. combination,
All methods of delivery and order of administration are conceivable.

In one embodiment of the present invention, the present invention further contemplates the treatment of diseases in which a combination of pharmaceutically active substances, which may be administered separately, is implicated. Relating to combining in the form of a kit. For example, the kit comprises (1) a neurotensin receptor ligand; and (2) a second pharmaceutically active compound.
It may comprise two separate pharmaceutical compositions. The kit also includes containers for the separate compositions, such as a divided bottle or a divided foil pack. Still other examples of containers include syringes, boxes, bags, and the like. Typically, the kit includes instructions for the administration of the separate components.
The form of the kit may be such that the separate components are administered, preferably in different dosage forms (eg, oral and parenteral), at different dosing intervals, or by the prescribing physician. If a titration of the components of
It is particularly convenient.

One example of a kit is a blister pack.
Blister packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packaging generally consists of a sheet of relatively rigid material, preferably coated with a foil of a transparent plastic material. During the packaging process, a recess is formed in the plastic foil. The recesses have the size and shape of the tablet or capsule to be packaged. The tablets or capsules are then placed in the recesses and a sheet of relatively stiff material is sealed against the plastic foil on the foil surface opposite the side on which the recesses were formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that a tablet or capsule can be removed from the blister package by applying a finger pressure to the recess to form a hole at the recess in the sheet. The tablet or capsule can then be removed from the hole.

[0030] The kit may include, for example, one that assists in remembering the number next to the tablet or capsule in the form of a number corresponding to the date of the treatment regimen in which the tablet or capsule so specified is to be taken. It may be desirable to give. Another example of such a memory aid is
For example, the calendar is printed on a card such as "first week, Monday, Tuesday, etc., second week, Monday, Tuesday, ...". Other variations of those that aid in memory will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on one day. Further, the daily dose of the neurotensin receptor ligand may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. It is. Anything that aids in memory should indicate this and assist in accurate administration of the active.

In another embodiment of the present invention, 1
Dispensers are provided that are designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is provided with a memory aid to further facilitate compliance with the regimen. One example of such a memory aid is:
It is a mechanical counter showing the number of daily doses dispensed. Another example of such memory aids is, for example, reading a date when the last daily dose was taken and / or coupled with a liquid crystal display or an audible attention signal to remind the date when the next dose should be taken. Battery-type microchip memory.

The neurotensin receptor ligand and other pharmaceutically active compounds can be administered to the patient, if desired, orally, rectally, parenterally (eg, intravenously, intramuscularly or subcutaneously), intrathecally, It can be administered intravaginally, intraperitoneally, intravesically, topically (eg, as a powder, ointment or drops), or as an oral or nasal spray.

Compositions suitable for parenteral injection may include sterile physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or may be reduced to sterile injectable solutions or dispersions. A sterile powder for the preparation. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, and vegetable oils such as olive oil. Injectable organic esters such as triglycerides or ethyl oleate are included. A preferred carrier is Myglyol®. Suitable fluidity can be achieved, for example, by using a coating such as lecithin.
It can be maintained by maintaining the required particle size in the case of dispersants and / or by using surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and / or dispersing agents. Prevention of the incorporation of microorganisms in these compositions can be accomplished by the addition of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical composition can be brought about by substances which can delay absorption, for example, aluminum monostearate and / or
Or it can be effected by the use of gelatin.

Solid dosage forms for oral administration include capsules,
Includes tablets, powders and granules. For such solid dosage forms, the active compound may be at least one inert conventional excipient (or carrier) such as sodium citrate or dibasic calcium phosphate or (a) a filler or extender, for example, Starch, lactose, sucrose, mannitol or silicic acid; (b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose or gum arabic; (c) humectants such as glycerol;
(D) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, some complex silicates or sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption enhancers, such as Quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol or glyceryl monostearate; (h) adsorbents, such as kaolin or bentonite; and / or (i) lubricants, such as talc, calcium stearate, It is mixed with magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules and tablets, the dosage forms may also contain a buffer.

A solid composition of a similar type may be used as a filler in filled soft and hard gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycols and the like. Is also good.

Solid dosage forms such as tablets, dragees, capsules and granules can be prepared with coatings or shells, such as enteric coatings, and others known in the art. They are,
Opacifiers may also be included, or compositions may be such that they release one or more active compounds in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame seed oil, Miglyol® , Glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or a mixture of these substances.

In addition to such inert diluents, the compositions can also include adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. Suspensions, in addition to the active compounds, suspending agents, for example,
It may contain ethoxylated isostearyl alcohol, polyoxyethylene sorbitol or sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth gum, or mixtures of these materials.

Compositions for rectal or vaginal administration may be prepared by incorporating the neurotensin receptor ligand and any additional compounds into a suitable nonirritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax. And they are solid at normal room temperature but liquid at body temperature, so that they melt in the rectum or vaginal cavity and release the neurotensin receptor ligand.

[0041] Dosage forms for topical administration of neurotensin receptor ligands include ointments, powders, sprays and inhalants. One or more compounds are mixed under sterile conditions with a physiologically acceptable carrier, and with any preservatives, buffers, and / or propellants that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The neurotensin receptor ligand can be administered to a patient at a dosage level ranging from about 0.1 to about 7,000 mg / day. A preferred dose range is about 1
約 about 100 mg / day. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determination of dosage ranges and optimal dosages for a particular patient is within the skill of the art in light of this disclosure.

The following paragraphs describe representative formulations, dosages, etc. useful for non-human animals. Administration of the neurotensin receptor ligand can be oral or parenteral, eg, by injection. When administered orally to a fixed amount of a neurotensin receptor ligand, generally an animal, such that a therapeutically effective amount is provided, it is usually from 0.01 to 1%.
000 mg / kg (body weight), preferably 0.1 to 50
A daily dose of mg / kg (body weight) is administered. Advantageously, one or more compounds can be included in the drinking water such that a therapeutic dose of one or more compounds is ingested with daily watering. The compound or compounds can be metered directly into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt). Conveniently, the compound or compounds can also be added directly to the feed, either neat or in the form of an animal feed additive, also referred to as a premix or concentrate. Premixes or concentrates in a carrier are more commonly used to include one or more compounds in the feed. Suitable carriers are
Water; various flours such as alfalfa flour, soy flour, cottonseed oil flour, linseed oil flour, corn cob flour and corn flour, molasses, urea, bone meal, and mineral compounds such as those commonly used in poultry feed. Such is the desired liquid or solid. A particularly effective carrier is the respective animal feed itself, ie, small amounts of such feed. The carrier facilitates uniform distribution of one or more compounds in the finished feed into which the premix is formulated. It is important that the compound or compounds be completely incorporated into the premix and subsequently into the feed. In this regard, one or more compounds are dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil, or the like, or in a volatile organic solvent, and then compounded with a carrier. Good. The proportion of the compound or compounds in the concentrate is adjusted by adjusting the amount of the active compound or compounds in the finished feed by combining an appropriate proportion of the premix with the feed;
It will be appreciated that the desired level of the compound or compounds may be obtained and may vary widely.

The high titer concentrate is formulated by the feed manufacturer with a protein carrier such as soybean oil flour or other flour as described above to produce a concentrate feed additive suitable for direct supply to animals. can do. In such cases, the animals are allowed to consume normal diet.
Alternatively, such concentrate additives can be added directly to the feed to produce a nutritionally balanced finished feed containing therapeutically effective levels of a compound of the present invention. The mixtures are completely blended by standard methods, such as in a V-blender, to ensure homogeneity.

If the feed additive is used as a final finishing material of the feed, it also helps to ensure a uniform distribution of the compound or compounds along the surface of the finished feed.

For parenteral administration in non-human animals, one or more compounds are prepared in the form of pastas or pellets and administered as implants, usually under the skin of the animal's head or ears. Can be.

Pasta formulations can be prepared by dispersing one or more compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil and the like.

Pellets containing a therapeutically effective amount of one or more compounds can be prepared by mixing the compound with a diluent, such as carbowax, carnauba wax, etc. Lubricants such as calcium can be added to improve the pelletizing process.

It is, of course, understood that more than one pellet may be administered to an animal to achieve the desired dose level. It has further been found that implants can also be given periodically during the treatment of the animal in order to maintain a suitable active substance level in the animal.

The term pharmaceutically acceptable salt or prodrug is within the scope of sound medical judgment and is suitable for use in patients without inappropriate toxicity, irritation, allergic reactions, etc. Salts and prodrugs of the compounds that correspond to different benefit / risk ratios and are effective for their intended use, as well as, where possible, zwitterionic forms of the compounds.

The term "salt" refers to the inorganic and organic salts of a compound. These salts can be used in situ during the final isolation and purification of the compound, or the purified compound,
Where appropriate, it can be prepared by separately reacting with a suitable organic or inorganic acid or base and isolating the salt thus formed. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
Oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, besylate, esylate, citrate, maleate, fumarate, succinate Acid salts, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate and the like. These include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, Non-toxic ammonium, quaternary ammonium and amine cations can be included, including but not limited to ethylamine and the like. For example,
SMBerge et al., “Pharmaceutical Salts,” J Pharm Sc
i, 66: 1-19 (1977).

The term “prodrug” refers to in vivo
Means a compound that is converted into a therapeutically active compound. The conversion can occur by various mechanisms, such as by hydrolysis in blood. For a discussion of the use of prodrugs, see T. Higuchi and W. Stella, “Pro-dr.
ugs as Novel Delivery Systems, ”ACS Symposium S
eries, and in Bioreversible Carriers in Drug Desig
n, Edward B. Roche, American Pharmaceutical Ass
Association and Pergamon Press, 1987, Volume 14.

For example, if a compound contains a carboxylic acid functional group, the prodrug may replace the hydrogen atom of the acid group with (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 5 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxy having 3 to 6 carbon atoms Methyl, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, 3 to 9 carbon atoms N- (alkoxycarbonyl) aminomethyl having 1- (N- (alkoxycarbonyl) amino) having 4 to 10 carbon atoms
Ethyl, 3-phthalidyl, 4-crotonolactonyl, γ
-Butyrolactone-4-yl, di-N, N- (C _1-
C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (such as β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ )
Alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl and substitution with groups such as piperidino-, pyrrolidino- or morpholino (C ₂ -C ₃ ) alkyl May be included.

Similarly, certain compounds have an alcohol function.
If included, the prodrug is the hydrogen atom of the alcohol group.
The child, (C₁-C₆) Alkanoyloxymethyl, 1-
((C ₁-C₆) Alkanoyloxy) ethyl, 1-methyl
Ru-1-((C₁-C₆) Alkanoyloxy) ethyl,
(C₁-C₆) Alkoxycarbonyloxymethyl, N-
(C₁-C₆) Alkoxycarbonylaminomethyl, suc
Shinoyl, (C₁-C₆) Alkanoyl, α-amino (C
₁-C_Four) Alkanoyl, arylacyl and α-amido
Noacyl or α-aminoacyl-α-aminoacyl
[However, the α-aminoacyl groups are each independently
Naturally present L-amino acid, P (O) (OH)_Two, -P
(O) (O ((C₁-C₆) Alkyl)_TwoOr glycos
Elimination of hydroxyl groups in the hemiacetal form of carbohydrates
Group generated by leaving)
It can be formed by transposing.

When a compound contains an amine function, a prodrug may be formed by replacing a hydrogen atom in the amine group with R-carbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R 'are each independently And (C ₁ −
C ₁₀₎ alkyl, (C ₃ -C ₇₎ cycloalkyl, or is selected from benzyl, R- carbonyl is a natural α- aminoacyl or natural α- aminoacyl - natural α
-Aminoacyl]; C (OH) C (O) OY wherein Y is H, (C ₁ -C ₆ ) alkyl or benzyl; -C (OY ₀ ) Y _{1 wherein} Y ₀ is (C ₁ -C ₄ )
And Y ₁ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl, or mono-N- or di-N, N- (C ₁ -C _{6)
Alkylaminoalkyl]; - C (Y 2)} Y 3 [ wherein, Y ₂ is H or methyl, Y ₃ is mono -N- or di _{-N, N- (C 1 -C 6} ) alkyl Amino, morpholino, piperidin-1-yl or pyrrolidin-1-yl].

The neurotensin receptor ligands can contain asymmetric or chiral centers and can exist in different stereoisomeric forms. All stereoisomers, as well as their mixtures, including racemic mixtures, are considered to form part of the invention. Furthermore, all geometric and positional isomers are contemplated in the present invention. For example, if a compound contains a double bond, both cis and trans, as well as mixtures, are contemplated.

Mixtures of isomers, including stereoisomers, can be separated into individual isomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. it can. Enantiomers convert the enantiomeric mixture into a mixture of diastereomers by reaction with a suitable optically active compound (eg, an alcohol), separate the diastereomers, and convert the individual diastereomers to the appropriate It can be separated by conversion (eg, hydrolysis) to the pure enantiomer. Furthermore, some compounds of the present invention may be atropisomers (eg, substituted biaryls) and are considered as part of this invention.

The neurotensin receptor ligand is water,
It may exist in the form of a solvate with a pharmaceutically acceptable solvent such as ethanol and the like, and also a non-solvate.
The present invention contemplates and encompasses both solvated and unsolvated forms.

It is possible that neurotensin receptor ligands can exist in various tautomeric forms.
All tautomers of the neurotensin receptor ligand are possible.

Those of skill in the art would understand that compound names included herein may be based on a particular tautomer of the compound. Although it is possible to use a compound name of only a specific tautomer, the compound name of the specific tautomer includes all tautomers, and all tautomers are It is considered a part of the present invention.

The invention disclosed herein may be synthesized in vitro using laboratory techniques as are well known to synthetic chemists; or in vitro, such as by metabolism, fermentation, digestion, and the like.
Also encompasses compounds synthesized using the vo technique. It is also envisioned that the compounds can be synthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically-labelled compounds, wherein two or more atoms differ in atomic mass or mass number from the atomic masses or mass numbers normally found most naturally in nature. It is consistent with a non-isotopically labeled compound except that it has been replaced with an atom having a mass number. Examples of isotopes that may be included in the compounds identified according to the present invention include: ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵
Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively, such as N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹³⁵ I and ³⁶ Cl. Neurotensin receptor ligands containing the aforementioned isotopes and / or other isotopes of other atoms, their prodrugs,
And pharmaceutically acceptable salts of their ligands or prodrugs are within the scope of the invention. Some isotopically labeled compounds of the present invention, for example those in which radioactive isotopes such as ³ H and ¹⁴ C are included, are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes, ie, ³ H and carbon-
14, ie, ¹⁴ C isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with deuterium, a heavier isotope such as ² H, has increased metabolic stability, eg, increased
It may provide some therapeutic benefit caused by in vivo half-life or reduced dosing requirements and may therefore be preferred in some cases. Isotopically-labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

The present invention relates to obesity, diabetes, sexual dysfunction,
It relates to the use of a neurotensin receptor ligand for treating atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia.

Further, a neurotensin receptor ligand,
In particular, neurotensin-2 receptor ligands include hyperthermia; hypothermia; gastrointestinal ulcer; substance abuse; depression; Alzheimer's disease; tardive dyskinesia; panic attacks; cholic); indigestion; pancreatitis; esophagitis; gastroparesis; schizophrenia, psychosis,
Neuropathies such as anxiety, manic depression, delirium, severe mental retardation, and dyskinesias such as Huntington's disease and Tourette's syndrome; viral and fungal infections, including HIV-1 and HIV-2; pain (ie, analgesia) Drugs); cancer (including gastrointestinal tumors); anorexia; bulimia;
Asthma; Parkinson's disease; acute heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina; myocardial infarction;
It can be used to treat inflammation; or benign prostatic hyperplasia.

The therapeutic methods of the present invention may also include combination therapies in which other pharmaceutically active compounds useful for treating obesity or other diseases are used in combination with a neurotensin receptor ligand.

Obese patients may be atherosclerosis,
Hypercholesterolemia, hypertriglyceridemia, hypertension, sexual dysfunction (including erectile dysfunction), insulin resistance, impaired glucose tolerance, diabetes [especially non-insulin dependent diabetes mellitus (NIDDM or type 2 diabetes)] It is known that the incidence of some diseases, such as nephropathy, neuropathy, retinopathy, cardiomyopathy, cataracts and diseases related to diabetes such as polycystic ovary syndrome, is higher. These diseases can be treated indirectly, by treating obesity with a neurotensin receptor ligand, or directly, by treating the particular disease itself with a neurotensin receptor ligand. it can. These diseases, even if they are not obese, can be treated with neurotensin receptor ligands.

In one embodiment of the present invention, obese patients or those at risk of becoming obese include: (1) a neurotensin receptor ligand; and (2) an obesity,
Diabetes (including (NIDDM) and conditions and diseases related to diabetes such as nephropathy, neuropathy, retinopathy, cardiomyopathy, cataract and polycystic ovary syndrome), atherosclerosis, hypercholesterolemia, Additional compounds useful in treating hypertriglyceridemia, sexual dysfunction (including erectile dysfunction), insulin resistance, or impaired glucose tolerance or combinations of compound combinations useful in treating these diseases. Can be administered.

Sexual dysfunction occurs in both men and women,
Includes hypoactive sexual desire disorder, anesthesia, and dyspareunia. Hypoactive sexual desire disorder is a disorder in which sexual fantasy and desire for sexual activity are permanently or recurrently reduced or absent, resulting in significant distress or interpersonal difficulties. Symptoms and signs of hypoactive sexual desire disorder include patients who complain of a lack of interest in sex even in normal sexual arousal situations. The disorder is usually associated with low sexual activity and often results in significant conflicts with partners. Anesthesia has reduced or no pleasure in sexual activity. Anesthesia is almost always classified as hypoactive sexual desire disorder, because decreased pleasure typically results in reduced desire. Intercourse pain is painful intercourse or attempted intercourse.

[0069] Erectile dysfunction is another example of sexual dysfunction. Erectile dysfunction, like obesity, is another condition that can cause severe emotional distress. Patients suffering from erectile dysfunction cannot erect and / or maintain the penis. Historically, erectile dysfunction has been thought to have biological and psychological components, and it is believed that more effort should be given to treating the psychological component of the condition. More recently, with the introduction of Viagra®, patients with this condition have been recommended for oral drug treatment.

Diabetes is more often found in obese patients than in non-obese patients. Early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and later on the use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone Despite discovery and use, treatment of diabetes remains unsatisfactory.

Currently, the use of insulin requires a large number of daily doses, usually by self-injection. Determining an appropriate insulin dose requires frequent quantification of sugar in urine or blood. Administration of an overdose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma or death. Treatment of non-insulin dependent diabetes mellitus (type 2 diabetes, NIDDM) usually consists of a diet, exercise, a combination of oral hypoglycemic drugs such as thiazolidenedione and, in more severe cases, insulin. However, clinically available hypoglycemic drugs may have side effects that limit their use, or certain drugs may not be effective for certain patients. In the case of insulin-dependent diabetes (type 1),
Insulin is the main course of treatment. There is a need for yet another hypoglycemic drug that has fewer side effects or succeeds if others fail.

Atherosclerosis, a disease of the arteries, has been identified as the leading cause of death in the United States and Western Europe. Pathological consequences leading to atherosclerosis and obstructive heart disease are well known. The earliest stage of this succession is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and the aorta. These lesions are yellow due to the presence of lipid deposits found predominantly in smooth muscle cells and in macrophages of the intimal layer of the arteries and aorta. Furthermore, it is postulated that most of the cholesterol found in those fat streaks in turn causes "fibrous plaques", which are derived from lipid-laden, accumulated arterial intimal smooth muscle cells. Consisting of extracellular lipids, collagen,
Surrounded by elastin and proteoglycans. Cells with added substrate form a fibrous cap that covers the deeper deposits of cell debris and more extracellular lipids. The lipids are mainly free and esterified cholesterol. Fibrous plaques are gradually formed, eventually becoming calcified and necrotic, and are thought to progress to "complicated lesions", which are malignant thrombi that characterize advanced atherosclerosis And explain the tendency toward arterial spasm and arterial occlusion.

Epidemiological evidence has established hyperlipidemia as a major risk factor for cardiovascular disease (CVD) due to atherosclerosis. In recent years, physician leaders have identified as an essential step in the prevention of CVD,
A new emphasis is on lowering plasma cholesterol levels, especially low density lipoprotein cholesterol. It is now known that the upper limit of “normal” is significantly lower than previously observed. As a result, the majority of the western population is now perceived to be at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being male. Cardiovascular disease is particularly prevalent among diabetics, at least in part, due to the presence of multiple independent risk factors in this population. General population, especially
Successful treatment of hyperlipidemia in diabetic patients is therefore of great medical importance.

Hypertension (ie, hypertension) is a condition that occurs in the human population as a secondary symptom to various other disorders, such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also found in many patients whose causative agent or disorder is unknown. Such "instinct" hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, but the relationship between these diseases has not been elucidated. Furthermore,
Many patients show symptoms of hypertension in the absence of any signs of any other disease or disorder.

It is known that hypertension can directly lead to heart failure, renal failure and stroke (cerebral hemorrhage). These conditions can cause the patient to die. Hypertension can also cause the development of atherosclerosis and coronary artery disease.
These conditions can gradually weaken the patient and cause death.

Although the exact cause of instinct hypertension is not known, a number of factors are thought to be responsible for the onset of the disease. Among these factors are stress, uncontrolled emotions, unregulated hormone release (renin,
Angiotensins, aldosterones), excess salt and water due to renal insufficiency, vascular thickening and hypertrophy that narrows blood vessels, and genetic factors.

The treatment of instinct hypertension is performed with the aforementioned factors in mind. Accordingly, a wide range of β-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensive drugs. Treatment of hypertension with these compounds has been shown to be beneficial in preventing short-term deaths such as heart failure, renal failure and cerebral hemorrhage.

[0078] Hypertension is associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary effect is to promote glucose utilization, protein synthesis, and the formation and storage of neutral lipids, is particularly important as it promotes vascular cell growth and increases renal sodium retention. Works. These latter functions are known to be responsible for hypertension as they can be performed without affecting glucose levels. Peripheral vascular growth, for example, can cause narrowing of peripheral capillaries,
Sodium retention increases blood volume. Therefore,
Reducing insulin levels in hyperinsulinemia patients can prevent abnormal blood vessel growth and renal sodium retention caused by high insulin levels, thereby alleviating hypertension.

The neurotensin receptor ligands can be used in combination with one or more compounds that are useful for treating obesity. Examples of a class of compounds that can be used to treat obesity include Ad
ipex®, Bontril®, Desoxyn Gra
one or more of an appetite suppressant such as dumet®, Fastin®, Ionamin® and Meridia®, and a lipase inhibitor such as Xenical® Active compounds are included.

Still other antiobesity agents that can be used in combination with the neurotensin receptor ligands include β
₃ adrenergic receptor agonist, cholecystokinin A agonist, monoamine reuptake inhibitor, sympathomimetic, serotonin agonist, dopamine agonist, melanocyte stimulating hormone receptor agonist or mimic, melanocyte stimulating hormone receptor analog Body, cannabinoid receptor antagonist, melanin-concentrating hormone antagonist, leptin, leptin analog, leptin receptor agonist, galanin antagonist, bombesin agonist, neuropeptide Y antagonist (NPY-1
And NPY-5), thyroid analogs, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, and Ciliary neurotrophic factors are included.

Particularly preferred anti-obesity agents which can be used in combination with the neurotensin receptor ligands include sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, orlistat (orlistat)
stat), ephedrine, leptin, phenylpropanolamine, pseudoephedrine, {4- [2- (2-
[6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl {acetic acid, {4-
[2- (2- [6-aminopyridin-3-yl] -2
(R) -hydroxyethylamino) ethoxy] phenyl} benzoic acid, {4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino)
Ethoxy] phenyl} propionic acid and {4- [2-
(2- [6-aminopyridin-3-yl] -2 (R)-
Hydroxyethylamino) ethoxy] phenoxydiacetic acid.

Examples of thyroid analogs that can be used in combination with a neurotensin receptor ligand include US Patent Application Nos. 60 / 178,968 and 60.
No. 177,987.

[0083] Examples of glucocorticoid receptor ligands that can be used in combination with neurotensin receptor ligands include US Patent Application Serial No. 60 / 132,1.
No. 30 disclosed therein.

Examples of neuropeptide Y antagonists that can be used in combination with neurotensin receptor ligands include WO 98/23603, US Pat.
No. 900,415, U.S. Pat. No. 5,914,329 and U.S. Reserved Patent Application No. 60 / 132,029 (NP
Y-5).

Examples of β ₃ adrenergic receptor agonists that can be used in combination with a neurotensin receptor ligand include those disclosed in WO 96/35671.

[0086] It can be used to treat obesity,
Yet another compound that can be used in combination with a neurotensin receptor ligand is WO98 / 4
Included are the compounds disclosed in US Pat.

Similarly, Viagra® which can be used to treat sexual dysfunction, especially erectile dysfunction
Compounds such as can also be used in combination with a neurotensin receptor ligand. Sexual dysfunction, especially
Other compounds that can be used to treat erectile dysfunction and that can be used in combination with neurotensin receptor ligands include apomorphine and I
C351 (ICOS). Sexual dysfunction, especially
One class of compounds that are useful for treating erectile dysfunction are phosphodiesterase V inhibitors. Examples of phosphodiesterase V inhibitors are described in US Pat. No. 5,272,1
No. 47 can be found.

In another embodiment of the present invention, the neurotensin receptor ligand can be administered in combination with a compound known to treat hypertension. Examples of types of compounds that can be used to treat hypertension include calcium blockers, ACE inhibitors,
Includes diuretics, angiotensin II receptor blockers, beta blockers and alpha adrenergic blockers. In addition, combinations of the above listed compounds have been used to treat hypertension. Some examples of specific compounds that can be used in combination with a neurotensin receptor ligand include quinapril; amlodipine, including the besylate salt; nifedipine; doxazosin, including the mesylate salt; and prazosin, including the hydrochloride salt. included.

In another embodiment, the neurotensin receptor ligand is impaired glucose tolerance, insulin resistance, insulin dependent diabetes (type 1) and non-insulin dependent diabetes (NIDDM or type 2 diabetes).
Can be used in combination with compounds useful for the treatment of diabetes, including Furthermore, considered to be included in the treatment of diabetes are complications of diabetes such as neuropathy, nephropathy, retinopathy, cardiomyopathy or cataract.

Can be used to treat diabetes
Moreover, representative agents that can be used in combination with neurotensin receptor ligands include insulin and insulin analogs (eg, LysPro insulin); GLP-1 (7-37) (insulinotropin)
And GLP-1 (7-36) -NH ₂ ; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepirid
e), repaglinide, meglitinide (me
glitinide); biguanides: metformin, phenformin, buformin; α2 antagonists and imidazolines: midaglizole, isaglidole, deriglidol
e), idazoxan, ephaloxane (efa)
roxan), fluparoxan; other insulin secretagogues: linogliride, A
-4166; glitazones (glitazones): ciglitazone (ciglitazone), pioglitazone (pioglitazon)
e), englitazone (englitazone), troglitazone (troglitazone), dalglitazone (darglitazone),
BRL49653; fatty acid oxidation inhibitor systems: clomoxir, etomoxir; α-glucosidase inhibitor systems: acarbose, micarbitol, miglitol, emiglitate, voglibose, MDL-25,637, Camiglibose, MDL-73,94
5; β agonist system: BRL35135, BRL373
44, Ro16-8714, ICI D7114, CL
316, 243; phosphodiesterase inhibitor system: L-
386, 398; lipid-lowering drug system: benfluorex (be
nfluorex); antiobesity drug system: fenfluramine and orlistat; vanadate and vanadium complex system (eg, Naglivan®) and peroxovanadium complex system; amylin antagonist system; glucagon antagonist system; gluconeogenesis inhibitor system Somatostatin agonist and antagonist systems; anti-lipolytic drug systems: nicotinic acid, acipimox, WAG994; and WO96 / 39385 and WO96 / 3938.
No. 4 includes, but is not limited to, glycogen phosphorylase inhibitor systems. Further contemplated in combination with the compounds of the present invention are:
Pramlintide acetate (Symlin ^™ ) and nateglinide.

Preferred examples of glycogen phosphorylase inhibitors which can be used in combination with the neurotensin receptor ligand in the present invention include 6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S)-
Benzyl-3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 2-bromo-6H-thieno [2,
3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxypyrrolidine-
1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 2-methyl-6H-thieno [2,3-
b] pyrrole-5-carboxylic acid [(1S) -benzyl-
3-((3R, 4S) -dihydroxypyrrolidine-1-
Yl)-(2R) -hydroxy-3-oxopropyl]
-Amide; (±) -2-methyl-6H-thieno [2,3
-B] pyrrole-5-carboxylic acid [1-benzyl-2-
((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-bromo-6H
-Thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl]-
Amide; 2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-
((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl]-
Amide; 2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-
((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2,4-dichloro-6H-thieno [2,3-b] pyrrole-5-carboxylate [(1S) -benzyl -3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; (±) -4H-thieno [3,2-b] pyrrole-5- Carboxylic acid [1-benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxy The acid [(1S) -benzyl-3-((3R, 4S)-
Dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S)-
Benzyl-3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; (±) -2-bromo-4H-furo [3,2-b ] Pyrrole-5-carboxylic acid [1-benzyl-2-((3R, 4S) -dihydroxypyrrolidine-]
1-yl) -2-oxoethyl] -amide; 2-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxypyrrolidine] -1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 6H-thieno [2,
3-b] Pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidine-
1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidine] -1-yl) -2-oxoethyl]
-Amide; 2-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-
((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2,4-dichloro-6H-thieno [2,3-b] pyrrole-5-carboxylate [(1S) -benzyl -2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl]
-Amide; 2-cyano-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-
(3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide; 2-chloro-6H-thieno [2,3
-B] pyrrole-5-carboxylic acid [(1S) -benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; 2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid Acid [(1S) -dimethylcarbamoyl-2-phenylethyl] -amide; 2-chloro-6H-
Thieno [2,3-b] pyrrole-5-carboxylic acid [(1
S) -benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxoethyl] -amide; 1
-｛(2S)-[(2-chloro-6H-thieno [2,3
-B] pyrrole-5-carbonyl) -amino] -3-phenylpropionyl} -piperidine-4-carboxylic acid ethyl ester; 2-bromo-6H-thieno [2,3-
b] pyrrole-5-carboxylic acid [(1S) -benzyl-
2- (3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide; 2-methyl-4H-furo [3,
2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidine-
1-yl) -2-oxoethyl] -amide; 2-trimethylsilanylethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-
(3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide; 2-ethynyl-6H-thieno [2,
3-b] Pyrrole-5-carboxylic acid [(1S) -benzyl-2- (3-hydroxyazetidin-1-yl) -2
-Oxoethyl] -amide; 2-fluoro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S)
-Benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2
-Cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide; 2-chloro -4H-Flo [3,2-b] pyrrole-
5-carboxylic acid [(1S) -benzyl-2-((3R,
4S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-chloro-4H-furo [3,
2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxypyrrolidine-
1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 1-{(2S)-[(2-chloro-6H
-Thieno [2,3-b] pyrrole-5-carbonyl)-
Amino] -3-phenylpropionyl} -piperidine-
4-carboxylic acid; 3-chloro-4H-thieno [3,2-
b] pyrrole-5-carboxylic acid [(1S) -benzyl-
2-((3R, 4S) -dihydroxypyrrolidine-1-
Yl) -2-oxoethyl] -amide; 3-chloro-4
H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl ] -Amide; 3-bromo-4H-
Thieno [3,2-b] pyrrole-5-carboxylic acid [(1
S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 3-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [ (1S) -benzyl-3-((3
R, 4S) -Dihydroxypyrrolidin-1-yl)-
(2R) -hydroxy-3-oxopropyl] -amide; 2-chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3
R, 4S) -Dihydroxypyrrolidin-1-yl)-
(2R) -hydroxy-3-oxopropyl] -amide; 2-chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3
R, 4S) -Dihydroxypyrrolidin-1-yl) -2
-Oxoethyl] -amide; 3-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S)-
Benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 3-
Methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-((3R, 4S)
-Dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 2-cyano-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl- 2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl]
-Amide; 2-cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-3-
((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl]-
Amide; 3-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3
R, 4S) -Dihydroxypyrrolidin-1-yl) -2
-Oxoethyl] -amide; 3-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S)-
Benzyl-3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-oxopropyl] -amide; 4H-1,7-dithia-4-azacyclopenta [a] pentalene -5-carboxylic acid [(1
S) -benzyl-3-((3R, 4S) -dihydroxypyrrolidin-1-yl)-(2R) -hydroxy-3-
Oxopropyl] -amide; 4H-1,7-dithia-4
-Azacyclopenta [a] pentalen-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl]-
Amide; 2-chloro-3-methyl-4H-thieno [3,
2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4S) -dihydroxypyrrolidine-
1-yl) -2-oxoethyl] -amide; 2-chloro-3-methyl-4H-thieno [3,2-b] pyrrole-
5-carboxylic acid [(1S) -benzyl-3-((3R,
4S) -Dihydroxypyrrolidin-1-yl)-(2
R) -Hydroxy-3-oxopropyl] -amide; 2
-Methylsulfanyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-
((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-bromo-4H
-Thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2- (1,1-dioxo-1-thiazolidine-3-yl) -2-oxoethyl]
-Amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; 2
-Bromo-4H-thieno [3,2-b] pyrrole-5
The carboxylic acid [(1S) -benzyl-2-((3R, 4
S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,
2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-((3R, 4R) -dihydroxypyrrolidine-
1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2- (4-hydroxypiperidin-1-yl) ) -2-oxoethyl] -amide; and pharmaceutically acceptable salts and prodrugs thereof,
And salts of these prodrugs.

The methods for preparing the glycogen phosphorylase inhibitors listed above can be found in US Patent Application Serial No. 60 / 157,148, filed September 30, 1999.

PCT Published Application WO 96/3 of the same assignee
No. 9384 and WO 96/39385 include new
Can be used in combination with rotensin receptor ligands
Another glycogen phosphorylase inhibitor that can be opened
It is shown. Yet another preferred glycogen phosphorylation
Rase inhibitors include 5-chloro-1H-indole-2
-Carboxylic acid [(1S)-((R) -hydroxydimethyi]
Rucarbamoylmethyl) -2-phenylethyl] -ami
C; 5,6-dichloro-1H-indole-2-carbo
Acid {(1S)-[(R) -hydroxy- (methoxymeth
Tylcarbamoyl) -methyl] -2-phenylethyl
-Amide; 5-chloro-1H-indole-2-carbo
Acid {(1S)-[(R) -hydroxy- (methoxymeth
Tylcarbamoyl) -methyl] -2-phenylethyl
-Amide; 5-chloro-1H-indole-2-carbo
Acid ((1S)-｛(R) -hydroxy-[(2-hydr
Roxyethyl) -methylcarbamoyl] -methyl} -2
-Phenylethyl) -amide; 5-chloro-1H-yne
Dole-2-carboxylic acid [(1S) -benzyl-3-
((3R, 4S) -dihydroxypyrrolidine-1-i
Ru)-(2R) -Hydroxy-3-oxopropyl]-
Amide; 5-chloro-1H-indole-2-carvone
Acid {(1S)-[(R) -hydroxy- (methylpyridyl)
2-N-ylcarbamoyl) -methyl] -2-phenyl
Ethyl} -amide; 5-chloro-1H-indole-2
-Carboxylic acid ((1S)-｛(R) -hydroxy- [me
Tyl- (2-pyridin-2-ylethyl) -carbamoy
5-methyl} -2-phenylethyl) -amide; 5-
Chloro-1H-indole-2-carboxylic acid [(1S)
-Benzyl- (2R) -hydroxy-3- (4-methyl
Piperazin-1-yl) -3-oxopropyl] -ami
Hydrochloride; 5-chloro-1H-indole-2-carbo
Acid [(1S) -benzyl- (2R) -hydroxy-3
-(3-hydroxyazetidin-1-yl) -3-oxo
Sopropyl] -amide; 5-chloro-1H-indole
-2-carboxylic acid ((1S) -benzyl- (2R) -h
Droxy-3-isoxazolidin-2-yl-3-o
Oxopropyl) -amide; 5-chloro-1H-indo
2-carboxylic acid ((1S) -benzyl- (2R)-
Hydroxy-3- [1,2] oxadinan-2-yl-
3-oxopropyl) -amide; 5-chloro-1H-i
Ndole-2-carboxylic acid [(1S) -benzyl- (2
R) -Hydroxy-3-((3S) -hydroxypyrroli
Zin-1-yl) -3-oxopropyl] -amide; 5
-Chloro-1H-indole-2-carboxylic acid [(1
S) -benzyl-3-((3S, 4S) -dihydroxy
Pyrrolidin-1-yl)-(2R) -hydroxy-3-
Oxopropyl] -amide; 5-chloro-1H-indo
2-carboxylic acid [(1S) -benzyl-3- (cy
-3,4-dihydroxypyrrolidin-1-yl)-
(2R) -Hydroxy-3-oxopropyl] -ami
C; 5-chloro-1H-indole-2-carboxylic acid
((1S) -benzyl- (2R) -hydroxy-3-mo
Ruphorin-4-yl-3-oxopropyl) -amide;
5-chloro-1H-indole-2-carboxylic acid [(1
S) -Benzyl-2- (3-hydroxyiminopyrrolidine
1-yl) -2-oxoethyl] -amide;
Rollo-1H-indole-2-carboxylic acid [2- (cis
-3,4-dihydroxypyrrolidin-1-yl) -2-
Oxoethyl] -amide; 5-chloro-1H-indo
2-carboxylic acid [2-((3S, 4S) -dihydro
Xypyrrolidin-1-yl) -2-oxoethyl] -a
Mido; 5-chloro-1H-indole-2-carboxylic acid
[(1S) -benzyl-2- (cis-3,4-dihydro
Xypyrrolidin-1-yl) -2-oxoethyl] -a
Mido; 5-chloro-1H-indole-2-carboxylic acid
[2- (1,1-dioxothiazolidin-3-yl)-
2-oxoethyl] -amide; 5-chloro-1H-yne
Dole-2-carboxylic acid (2-oxo-2-thiazolidy
-3-ylethyl) -amide; 5-chloro-1H-i
Ndole-2-carboxylic acid [(1S)-(4-fluoro
Benzyl) -2- (4-hydroxypiperidine-1-i
L) -2-oxoethyl] -amide; 5-chloro-1H
-Indole-2-carboxylic acid [(1S) -benzyl-
2-((3RS) -hydroxypiperidin-1-yl)
-2-oxoethyl] -amide; 5-chloro-1H-i
Indole-2-carboxylic acid [2-oxo-2-((1R
S) -Oxo-1-thiazolidin-3-yl) -ethyl
] -Amide; 5-chloro-1H-indole-2-ca
Rubonic acid [(1S)-(2-fluorobenzyl) -2-
(4-hydroxypiperidin-1-yl) -2-oxo
Ethyl] -amide; 5-chloro-1H-indole-2
-Carboxylic acid [(1S) -benzyl-2-((3S, 4
S) -Dihydroxypyrrolidin-1-yl) -2-oxo
Soethyl] -amide; 5-chloro-1H-indole-
2-carboxylic acid [(1S) -benzyl-2- (3-hydrido)
Roxyazetidin-1-yl) -2-oxoethyl]-
Amide; 5-chloro-1H-indole-2-carvone
The acid [(1S) -benzyl-2- (3-hydroxyimino)
Azetidin-1-yl) -2-oxoethyl] -ami
C; 5-chloro-1H-indole-2-carboxylic acid
[(1S) -benzyl-2- (4-hydroxyiminopi
Peridin-1-yl) -2-oxoethyl] -amide;
5-chloro-1H-indole-2-carboxylic acid [1-
Benzyl-2- (3-hydroxypyrrolidine-1-i
L) -2-oxoethyl] amide; 5-chloro-1H-
Indole-2-carboxylic acid [(1S)-((R) -H
Droxydimethylcarbamoylmethyl) -2-phenyl
Ethyl] -amide; 5-chloro-1H-indole-2
-Carboxylic acid [(1S)-((R) -hydroxy- (me
Toximethylcarbamoyl) -methyl) -2-phenyl
Ethyl] -amide; 5-chloro-1H-indole-2
-Carboxylic acid [(1S) -benzyl-3- (3-hydro-
Xixazetidin-1-yl)-(2R) -hydroxy-
3-oxopropyl] -amide; 5-chloro-1H-i
Ndole-2-carboxylic acid [(1S)-((R) -hydr)
Roxy- [methyl- (2-hydroxyethyl) -carba
Moyl] -methyl) -2-phenylethyl] -amide;
5-chloro-1H-indole-2-carboxylic acid [(1
S) -benzyl- (2R) -hydroxy-3-((3
S) -Hydroxypyrrolidin-1-yl) -3-oxo
Propyl] -amide; 5-chloro-1H-indole-
2-carboxylic acid [(1S) -benzyl- (2R) -hydride
Roxy-3-((3S, 4S) -dihydroxypyrrolidine
1-yl) -3-oxopropyl] -amide; 5-
Chloro-1H-indole-2-carboxylic acid [(1S)
-Benzyl-3- (cis-3,4-dihydroxypyrroli
Zin-1-yl)-(2R) -hydroxy-3-oxo
Propyl] -amide; 5-chloro-1H-indole-
2-carboxylic acid [1-benzyl-2- (3-hydroxy
Pyrrolidin-1-yl) -2-oxoethyl] -ami
C; 5-chloro-1H-indole-2-carboxylic acid
[(1S) -benzyl-2- (cis-3,4-dihydro
Xypyrrolidin-1-yl) -2-oxoethyl] -a
Mido; 5-chloro-1H-indole-2-carboxylic acid
[(1S)-(4-fluorobenzyl-2- (4-hydrido)
Roxypiperidin-1-yl) -2-oxoethyl]-
Amide; 5-chloro-1H-indole-2-carvone
Acid (2-oxo-2-thiazolidine-3-ylethyl)
-Amide; 5-chloro-1H-indole-2-carbo
Acid [(1S) -benzyl-2- (3-hydroxyazene)
Thidin-1-yl) -2-oxoethyl] -amide; 5
-Chloro-1H-indole-2-carboxylic acid [(1
S) -benzyl-2- (3-hydroxyiminoazetidi
1-yl) -2-oxoethyl] -amide;
Rollo-1H-indole-2-carboxylic acid [(1S)-
Benzyl-2-((3S, 4S) -dihydroxypyrroli
Zin-1-yl) -2-oxoethyl] -amide; and
And pharmaceutically acceptable salts and prodrugs thereof,
And salts of these prodrugs.

Any glycogen phosphorylase inhibitor may be a compound (active substance) in the combination aspect of the present invention.
Can be used as Glycogen phosphorylase inhibition is readily ascertained by those skilled in the art according to standard assays (eg, Pesce et al., (1977) Clinic).
al Chemistry 23: 1711-1717). A variety of glycogen phosphorylase inhibitors have been described above, however, other glycogen phosphorylase inhibitors include
It will be known to those skilled in the art (eg, WO 95/243).
91-A and U.S. Pat. No. 5,952,363). The following document also discloses glycogen phosphorylase inhibitors that can be used in the present invention. US Patent No. 5,998,463;
3-isopropyl-4- (2-chlorophenyl) -1,
Oikanomakos et al., Protein Science, 1999 8 (1) which discloses 4-dihydro-1-ethyl-2-methylpyridine.
0) 1930-1945; WO9524391; WO97090
No. 40; WO9840353; WO9850359
No .: WO 9731901; EP 840050; and Hoover et al., J. Med. Chem., 1998, 41, 2934-2938.

The neurotensin receptor ligand may be used in combination with an aldose reductase inhibitor. Aldose reductase inhibitors constitute a class of compounds whose usefulness in treating conditions due to diabetic complications such as diabetic neuropathy and nephropathy has become widely known. Such compounds are well known to those skilled in the art and are easily identified by standard biological tests. For example, the aldose reductase inhibitor zopolrestat, 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-
[[5- (trifluoromethyl) -2-benzothiazolyl] methyl]-and related compounds are disclosed in U.S. Pat.
No. 939,140.

The aldose reductase inhibitors are contemplated for use in lowering mammalian lipid levels. See, for example, US Pat. No. 4,492,706 and E.
See P0310931A2.

US Pat. No. 5,064,830 discloses the use of certain oxophthalazinylacetate aldose reductase inhibitors, including zopolrestat, to lower blood uric acid levels.

US Pat. No. 5,391,55 to the same assignee.
No. 1 includes a method for lowering human blood lipid levels.
The use of certain aldose reductase inhibitors, including zopolrestat, has been disclosed. The disclosure states that the therapeutic utility derives from the treatment of diseases caused by increased triglyceride levels in the blood, including thrombosis, atherosclerosis, myocardial infarction and angina pectoris It has been shown to include cardiovascular diseases such as A preferred aldose reductase inhibitor is zopolrestat.

The term aldose reductase inhibitor means a compound that inhibits the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase. Any aldose reductase inhibitor can be used in combination with a neurotensin receptor ligand. Aldose reductase inhibition is readily ascertained by those skilled in the art according to standard assays (J. Malone, Diabetes, 29: 861-864 (1980) “Red Cel.
l Sorbitol, an Indicator of Diabetic Control ”).
A variety of aldose reductase inhibitors are described herein, however, other aldose reductase inhibitors useful in some of the compositions and methods of the invention will be known to those of skill in the art.

The activity of an aldose reductase inhibitor in a tissue may reduce sorbitol in the tissue (ie, by inhibiting additional production of sorbitol as a result of inhibiting aldose reductase) or reducing fructose in the tissue (aldose). Inhibiting sorbitol production as a result of inhibiting reductase,
Consequently, it can be measured by examining the amount of aldose reductase inhibitor required (by inhibiting fructose production).

Accordingly, examples of aldose reductase inhibitors useful in some of the compositions, combinations and methods of the present invention include: 3- (4-bromo-2-fluorobenzyl)-
3,4-dihydro-4-oxo-1-phthalazineacetic acid (ponalrestat, US Pat.
No. 528); N [[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine (tolrestat, US 4,60
0,724); 5-[(Z, E) -β-methylcinnamylidene]
-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, US 4,464,3)
No. 82, US 4,791,126, US 4,831,
No. 045); 3- (4-bromo-2-fluorobenzyl) -7
-Chloro-3,4-dihydro-2,4-dioxo-1
(2H) -quinazolineacetic acid (zenarestat
t), US Pat. Nos. 4,734,419 and 4,883,
No. 800); 2R, 4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (US 4,883,4
No. 10); 2R, 4R-6,7-dichloro-6-fluoro-
4-hydroxy-2-methylchroman-4-acetic acid (US
No. 4,883,410); 3,4-dihydro-2,8-diisopropyl-3
7. -oxo-2H-1,4-benzoxazine-4-acetic acid (US Pat. No. 4,771,050); 3,4-dihydro-3-oxo-4-[(4,
5,7-trifluoro-2-benzothiazolyl) methyl] -2H-1,4-benzothiazine-2-acetic acid (SP
R-210, US Pat. No. 5,252,572); 9. N- [3,5-dimethyl-4-[(nitromethyl) sulfonyl] phenyl] -2-methylbenzeneacetamide (ZD5522, US Pat. Nos. 5,270,342 and 5,430,060); (S) -6-fluorospiro [chroman-4,
10. 4'-Imidazolidine] -2,5'-dione (sorbinil, US 4,130,714); 11. d-2-methyl-6-fluorospiro (chroman-4 ′, 4′-imidazolidine) -2 ′, 5′-dione (US Pat. No. 4,540,704); 2-fluorospiro (9H-fluorene-9,
4'-Imidazolidine) 2 ', 5'-dione (US 4,
No. 438, 272); 2,7-difluorospiro (9H-fluorene-9,4'-imidazolidine) 2 ', 5'-dione (U
S4,436,745, US4,438,272
No.); 2,7-difluoro-5-methoxyspiro (9
H-fluorene-9,4'-imidazolidin) 2 ',
5'-dione (US 4,436,745, US 4,4
No. 38, 272); 7-fluorospiro (5H-indenol [1,2-b] pyridine-5,3′-pyrrolidine) 2,
5'-dione (US 4,436,745, US 4,4
38, 272); d-cis-6'-chloro-2 ', 3'-dihydro-2'-methylspiro- (imidazolidin-4,4'
-4'-H-pyrano (2,3-b) pyridine) -2,5
-Diones (US 4,980,357); Spiro [imidazolidine-4,5 '(6H)-
Quinoline] 2,5-dione-3′-chloro-7 ′, 8 ′
-Dihydro-7'-methyl- (5'-cis) (US 5,
No. 066,659); (2S, 4S) -6-fluoro-2 ', 5'-
Dioxospiro (chroman-4,4'-imidazolidin) -2-carboxamide (US 5,447,946)
No.); 2-[(4-bromo-2-fluorophenyl)
Methyl] -6-fluorospiro [isoquinoline-4 (1
H), 3'-Pyrrolidine] -1,2 ', 3,5' (2
H) -Tetron (ARI-509, US 5,037,8)
No. 31); 20. 3,4-dihydro-3- (5-fluorobenzothiazol-2-ylmethyl) -4-oxophthalazin-1-ylacetic acid; 3- (5,7-difluorobenzothiazole-
21. 2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid; 3- (5-chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazine-
22. 1-ylacetic acid; 3- (5,7-dichlorobenzothiazole-2
23. -ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid; 25. 3,4-dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) phthalazin-1-ylacetic acid; 26. 3,4-dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-ylacetic acid; 27. 3- (5,7-Difluorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid; 28. 3- (5-chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid; 3- (5,7-dichlorobenzoxazole-
29. 2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid; Zopolrestat; 1-phthalazineacetic acid, 3,4
-Dihydro-4-oxo-3-[[5- (trifluoromethyl) -2-benzothiazolyl] methyl]-; and pharmaceutically acceptable salts and prodrugs thereof, and salts of these prodrugs. .

Aldose reductase inhibitors 20 to 29
Is disclosed in PCT Publication WO 99/26659. Neurotensin receptor ligands can also be used in combination with sorbitol dehydrogenase inhibitors. Sorbitol dehydrogenase inhibitors reduce fructose levels and are used to treat or prevent complications of diabetes such as neuropathy, retinopathy, nephropathy, cardiomyopathy, microangiopathy and macroangiopathy . US Patent 5,728,7
No. 04 and 5,866,578 disclose compounds and methods for treating diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. The compounds disclosed in these patents and other sorbitol dehydrogenase inhibitors can be used in the present invention in combination with a neurotensin receptor ligand.

The neurotensin receptor ligand can also be used in combination with a glucocorticoid receptor antagonist. Glucocorticoid receptor (GR)
Is present in glucocorticoid-responsive cells, where it is present in an inactive state in the cytosol until it is stimulated by an agonist. When stimulated,
The glucocorticoid receptor moves to the cell nucleus, where
It interacts specifically with DNA and / or one or more proteins and regulates transcription in a glucocorticoid-responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors API and N
Fκ-β. Since such an interaction causes the inhibition of API and NFκ-β mediated transcription,
It is thought to be involved in the anti-inflammatory activity of glucocorticoids administered endogenously. In addition, glucocorticoids may act physically independently of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. There are a number of synthetic glucocorticoid receptor agonists, including dexamethasone, prednisone, and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and producing GR-mediated consequences, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist. GR antagonists can be used in the treatment of diseases related to excess or deficiency of glucocorticoids in the body. As such, they include the following: obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration (Eg, Alzheimer's disease and Parkinson's disease), cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, weakness, inflammatory diseases (osteoarthritis, rheumatoid arthritis, asthma and rhinitis), adrenal insufficiency, viral infection, immunity Insufficiency, immune regulation, autoimmune disease, allergy, wound healing, compulsive behavior,
It can be used to treat multidrug resistance, addiction, mental illness, anorexia, cachexia, post-traumatic stress syndrome, post-operative fracture, medical catabolism, and prevention of muscle weakness.

An example of a preferred glucocorticoid receptor antagonist that can be used in combination with a neurotensin receptor ligand is described in US Patent Application Ser.
/ 132,130.

The neurotensin receptor ligand can also be used in combination with a sodium-hydrogen exchange transporter type 1 (NHE-1) inhibitor. Preferred NHE-1 inhibitors that can be used in combination with a neurotensin receptor ligand are described in PCT Publication WO 99/43663.
Can be found in the issue.

Furthermore, the neurotensin receptor ligand can be used in combination with a thyroid analog. In general, thyroid hormones, specifically biologically active iodothyronine, are understood to be critical for maintaining normal development and metabolic homeostasis. Thyroid hormone stimulates the metabolism of cholesterol to bile acids,
Facilitates the lipolytic response of fat cells to other hormones. U.S. Patent Nos. 4,766,121; 4,826,876.
No. 4,910,305; and 5,061,7
No. 98 discloses some thyroid hormone mimics (thyroid analogs), namely 3,5-dibromo-3 ′-[6-oxo-3 (1H) -pyridazinylmethyl] -thyronine. I have. U.S. Patent No. 5,284,971 discloses certain thyroid-like cholesterol-lowering drugs, i.e., 4- (3-cyclohexyl-4-hydroxy or -methoxyphenylsulfonyl) -3,5-dibromophenylacetic acid compounds. ing. US Patent 5,4
Nos. 01,772; 5,654,468; and 5,569,674 disclose certain thyroid analogs that are lipid-lowering drugs, ie, heteroacetic acid derivatives. In addition, some oxamic acid derivatives of thyroid hormone are known in the art. For example,
N. Yokoyama et al., Journal of Medicinal Chemistry, 3
8 (4): 695-707 (1995) on published papers, the -CH ₂ groups of metabolites in the naturally occurring of T ₃ is replaced by -NH groups, that cause -HNCOCO ₂ H It has been described. Similarly, RESTeele et al.
sional Service (Atherosclerosis X) 1066: 321-324 (19
95), and ZFStephan et al.
A paper published in therosclerosis, 126: 53-63 (1996) describes some oxamic acid derivatives that are useful as lipid-lowering thyroid mimetics and do not have undesirable cardiotonic activity.

Further, neurotensin receptor ligands include cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, in particular, HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors, HMG-Co
A reductase and synthase gene expression inhibitor, CE
TP inhibitor, bile acid sequesterant
s), fibrates, ACAT inhibitors, squalene synthetase inhibitors, antioxidants and other agents such as niacin. Neurotensin receptor ligands can also be administered in combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly referred to as nutraceuticals and include, for example, garlic extract, Benecol® and niacin.

Specific cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors are described in detail below. Still other cholesterol absorption inhibitors are well known to those skilled in the art and are described, for example, in WO 94/00480.

[0109] Any HMG-CoA reductase inhibitor can be used as an additional compound in the combination therapy aspect of the present invention. The term HMG-CoA reductase inhibitor means a compound that inhibits the biotransformation of hydroxymethylglutaryl coenzyme A to mevalonic acid, catalyzed by the enzyme HMG-CoA reductase. Such inhibition can be readily ascertained by those skilled in the art according to standard assays (eg, Methods of E.
nzymology, 71: 455-509 (1981); and references cited therein). A variety of these compounds are described and discussed below. U.S. Pat. No. 4,231,938 discloses Aspergillus, such as lovastatin.
lus) Some compounds are disclosed which are isolated after cultivation of microorganisms belonging to the genus Lus). Further, U.S. Pat.
No. 784 discloses synthetic derivatives of the foregoing compounds, such as simvastatin. Further, U.S. Pat.
No. 739,073 includes fluvastatin (fluvastati
Some substituted indoles such as n) are disclosed.
Further, U.S. Pat. No. 4,346,227 discloses ML-236B derivatives such as pravastatin. Furthermore, EP 491,226 discloses some pyridyl dihydroxyheptenoic acids such as rivastatin. Further, U.S. Pat.
7,576 includes atorvastatin
Some 6- [2- (substituted pyrrol-1-yl) such as
-Alkyl] -pyran-2-ones are disclosed. Other HMG-CoA reductase inhibitors will be known to those skilled in the art. Examples of commercially available products containing an HMG-CoA reductase inhibitor that can be used in combination with the compounds of the present invention include Baycol®, Lescol®, Lipitor®, Mevacor® , Pravachol® and Zocor®.

[0110] Any HMG-CoA synthase inhibitor can be used as the second compound in the combination therapy aspect of the present invention. The term HMG-CoA synthase inhibitor means a compound that inhibits the biosynthesis of hydroxymethylglutaryl coenzyme A from acetyl coenzyme A and acetoacetyl coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition can be readily ascertained by those skilled in the art according to standard assays (eg, Methods of Enzymology, 35: 155-160 (19
75); and Methods of Enzymology, 110: 19-26 (198
5); and references cited therein). A variety of these compounds are described and discussed below. U.S. Pat. No. 5,120,729 discloses some beta-lactam derivatives. U.S. Pat. No. 5,064,856 discloses certain spirolactone derivatives produced by culturing microorganism MF5253. U.S. Pat. No. 4,847,271 discloses 11- (3-hydroxymethyl-4-oxo-2-oxetile) -3,
Some oxetane compounds have been disclosed, such as 5,7-trimethyl-2,4-undecadienoic acid derivatives. Other HMG-CoA synthase inhibitors will be known to those skilled in the art.

Any compound that decreases HMG-CoA reductase gene expression can be used as an additional compound in the combination therapy aspect of the present invention. These substances may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA, or they may be HMG-C
It may be a translation inhibitor that prevents translation of mRNA encoding oA reductase into protein. Such inhibitors may directly affect transcription or translation, or may be biotransformed by one or more enzymes in the cholesterol biosynthesis cascade to compounds having the aforementioned properties; Or it may result in the accumulation of isoprene metabolites having the aforementioned activities. Such adjustments are readily ascertained by one skilled in the art according to standard assays (Methods of E.
nzymology, 110: 9-19 1985). Some such compounds are described and discussed below, however,
Inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. US Patent 5,041,43
No. 2 discloses some 15-substituted lanosterol derivatives. Other oxygenated sterols that inhibit HMG-CoA reductase biosynthesis are EIMercer (Prog. L
ip. Res., 32: 357-416 1993).

[0112] Any compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the present invention. The term CETP inhibitor refers to cholesterol ester transfer protein (CET)
P) -mediated compounds that inhibit the transport of various cholesterol esters and triglycerides from HDL to LDL and VLDL. A variety of these compounds are described and discussed below, however, other CETP inhibitors will be known to those skilled in the art. US Patent No. 5,512,548 discloses some polypeptide derivatives which are active as CETP inhibitors, but some CE derivatives of cholesterol esters are disclosed.
TP-inhibiting rosenonolactone derivatives and phosphoric acid-containing analogues are described, respectively, in J. Antibiot., 49 (8): 815-816 (1996).
And Bioorg. Med. Chem. Lett .; 6: 1951-1954 (1996). Other CETP inhibitors that can be used in combination with a neurotensin receptor ligand include
WO99 / 20302, EP796846, EP8
No. 18197, EP 818448, WO 99/142
No. 04, WO99 / 41237, WO95 / 0475
No. 5, WO96 / 15141, WO96 / 05227
No., DE19704244, DE19741051
No., DE19741399, DE19704243
No., DE19709125, DE19627430
No., DE 19832159, DE 19741400
No., JP11049743 and JP09090515
No. 5. Preferred CETPs that can be used in combination with a neurotensin receptor ligand
Inhibitors include [2R, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-ethyl-6-trifluoromethyl-3,4-
Dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-methoxymethyl-6-trifluoromethyl-
3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-
Bis-trifluoromethylbenzyl) -methoxycarbonylamino] -2-ethyl-6-trifluoromethyl-
3,4-dihydro-2H-quinoline-1-carboxylic acid 2
-Hydroxyethyl ester; [2S, 4S] 4-
[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-
[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4 − [(3,
5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-
[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4 −
[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-
1-carboxylic acid isopropyl ester; [2S, 4S]
4-[(3,5-bistrifluoromethylbenzyl)-
Methoxycarbonylamino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 2-cyclopropyl-4-[(3,5-dichloro Benzyl)-
Methoxycarbonylamino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5
-Bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester; [2S, 4S] 4-
[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4
S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-
Quinoline-1-carboxylic acid isopropyl ester; [2
R, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-ethyl-
6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2
S, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-
2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino] -2-
Ethyl-6-trifluoromethyl-3,4-dihydro-
2H-quinoline-1-carboxylic acid 2-hydroxyethyl ester; [2S, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino]
-2-cyclopropyl-6-trifluoromethyl-3,
4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino]
-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino ] -2-
Cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-[(3,5-bistrifluoromethylbenzyl) -methoxycarbonylamino]- 2
-Ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester;
And pharmaceutically acceptable salts and prodrugs thereof, and salts of these prodrugs.

Any ACAT inhibitor can serve as an additional compound in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to the enzyme acyl-CoA:
A compound that inhibits intracellular esterification of dietary cholesterol by cholesterol acyltransferase. Such inhibition can be achieved by those skilled in the art
Heider as described in of Lipid Research., 24: 1127 (1983).
It can be easily ascertained according to standard assays such as those described above. A variety of these compounds are described and discussed below, however, other ACAT inhibitors are:
It will be known to those skilled in the art. US Patent 5,510,3
No. 79 discloses some carboxysulfonates, but WO96 / 26948 and WO96 / 1.
No. 0559 both disclose urea derivatives having ACAT inhibitory activity.

Any compound having activity as a squalene synthetase inhibitor can serve as an additional compound in the combination therapy aspect of the present invention. The term squalene synthetase inhibitor means a compound that inhibits the condensation of two molecules of farnesyl pyrophosphate to form squalene, a reaction catalyzed by the enzyme squalene synthetase. Such inhibition is readily ascertained by those skilled in the art according to standard methods (Methods
of Enzymology, 15: 393-454 (1969); and Methods of
Enzymology, 110: 359-373 (1985); and references cited therein). A summary of squalene synthetase inhibitors follows Curr. Op. Ther. Patents, 861-4, (1993). EP-A-0567026 A1 discloses some 4,4 as squalene synthetase inhibitors.
1-benzoxazepine derivatives and their use in the treatment of hypercholesterolemia and as fungicides are disclosed. European Patent Application Publication No. 06453
No. 78A1 discloses certain 7- or 8-membered heterocycles as squalene synthetase inhibitors and their use in the treatment and prevention of hypercholesterolemia and fungal infections. European Patent Application No. 0645
377A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful in the treatment of hypercholesterolemia or coronary atherosclerosis. EP-A-0611749 A1 states that
Certain substituted amino acid derivatives useful in the treatment of atherosclerosis have been disclosed. European Patent Application Publication No. 07
05607A2 discloses some fused 7- or 8-membered heterocyclic compounds useful as antihypertriglyceridemic agents. PCT Publication No. WO 96/09827 discloses certain combinations of cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors, including benzoxazepine and benzothiazepine derivatives. EP-A-0 701 725 A1 states that
Methods for making some optically active compounds, including benzoxazepine derivatives, having plasma cholesterol and triglyceride lowering activity are disclosed. Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia, and to help prevent or treat atherosclerosis include Colestid®, LoCholest® ) And Questran (R); bile acid segregants; and fibric acid derivatives such as Atromid (R), Lopid (R) and Tricor (R). These compounds can also be used in combination with a neurotensin receptor ligand.

Neurotensin receptor ligands may be caused by the presence of excess triglycerides, free fatty acids, cholesterol, cholesterol esters or glucose, especially obesity, hyperlipidemia, hyperlipoproteinemia,
It is also conceivable that it is administered together with lipase inhibitors and / or glucosidase inhibitors typically used in the treatment of conditions including Syndrome X and the like.

In combination with a neurotensin receptor ligand, any lipase inhibitor or glucosidase inhibitor can be used. Preferred lipase inhibitors include gastric or pancreatic lipase inhibitors such as orlistat. Preferred glucosidase inhibitors include amylase inhibitors.

Lipase inhibitors are compounds that inhibit the metabolic degradation of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs by a two-step process involving acylation of the active serine residue of the lipase enzyme. This results in the production of a fatty acid-lipase hemiacetal intermediate, which in turn degrades to release diglycerides. After further deacylation, the lipase-fatty acid intermediate decomposes to yield free lipase, monoglycerides and fatty acids. The resulting free fatty acids and monoglycerides are contained in bile acid-phospholipid micelles, which are subsequently absorbed at the brush border level of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Thus, compounds including lipase inhibitors that selectively limit or inhibit the absorption of ingested fat precursors are useful in treating conditions including obesity, hyperlipidemia, hyperlipoproteinemia, syndrome X, and the like. Useful.

Pancreatic lipase is derived from triglyceride
Mediates the metabolic degradation of fatty acids at the-and 3-carbon positions.
The main site of metabolism of ingested fat is in the duodenum and proximal jejunum, usually by pancreatic lipase, which is secreted in excess of the amount required for fat breakdown in the upper small intestine. Inhibitors are useful in the treatment of obesity and other related conditions, as pancreatic lipase is a key enzyme required for absorption of food triglycerides.

Gastric lipase accounts for about 10-40% of dietary fat.
Is an immunologically distinct lipase involved in the digestion of lipase.
Gastric lipase is secreted in response to mechanical stimulation, food intake, the presence of a fatty diet or by sympathetic substances. Gastric lipolysis of ingested fats is physiologically important in the supply of fatty acids necessary to cause pancreatic lipase activity in the intestine, and in various physiological and pathological conditions related to renal dysfunction. It is also important for fat absorption. For example, CKAbrams et al., Gastroenterology, 92, 125
(1987).

A variety of lipase inhibitors are known to those skilled in the art. However, in some implementations of the methods, pharmaceutical compositions and kits of the present invention, preferred lipase inhibitors are generally lipstatin, tetrahydrolipstatin (orlistat), FL-386,
WAY-121898, Bay-N-3176, valilactone, esterasti (esterasti)
n), an inhibitor selected from the group consisting of ebelactone A, ebelactone B and RHC80267.

The pancreatic lipase inhibitor lipstatin 2
S, 3S, 5S, 7Z, 10Z) -5-[(S) -2-
Formamide-4-methylvaleryloxy] -2-hexyl-3-hydroxy-7,10-hexadecanoate lactone and 2S, 3S, 5S) -5-[(S) -2, which is tetrahydrolipstatin (orlistat) -Formamido-4-methylvaleryloxy] -2-hexyl-3-hydroxyhexadecanoic acid lactone, and various substituted N-formylleucine derivatives and their stereoisomers are disclosed in U.S. Patent No. 4,598,089. ing.

The pancreatic lipase inhibitor FL-386, 1-
[4- (2-methylpropyl) cyclohexyl] -2-
[(Phenylsulfonyl) oxy] -ethanone and various substituted sulfonate derivatives related thereto are disclosed in U.S. Pat. No. 4,452,813.

The pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenyl-4-methylpiperidine-
1-ylcarboxylates and various carbamates and pharmaceutically acceptable salts associated therewith are described in U.S. Patent Nos. 5,512,565; 5,391,571.
No. 5,602,151.

The lipase inhibitor Bay-N-3176, N-3-trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylurea, and various urea derivatives related thereto are disclosed in US Pat. , 40
No. 5,644.

The pancreatic lipase inhibitor valilactone and a method for its production by microbial culture of Actinomycetes strain MG147-CF2 is described in Kitahara et al., J. Antib.
iotics, 40 (11), 1647-1650 (1987).

The lipase inhibitor esteracin (esteraci)
n), and some methods for their production by microbial culture of Streptomyces strain ATCC 31336, are disclosed in U.S. Patent Nos. 4,189,438 and 4,242,453.

Pancreatic lipase inhibitors ebelactone A and ebelactone B, and Actinomycetes strain MG7-G
The production method by microbial culture is described in Umezawa et al.
Antibiotics, 33, 1594-1596 (1980).
The use of everaveractones A and B in inhibiting monoglyceride formation is disclosed in Japanese Patent Publication No. 08-143457, published June 4, 1996.

The lipase inhibitor RHC80267, cyclo-O, O '-[(1,6-hexanediyl) -bis (iminocarbonyl)] dioxime and various bis (iminocarbonyl) dioximes related thereto, were obtained from Peters
en et al., Liebig's Annalen, 562, 205-229 (1949). The ability of RHC80267 to inhibit the activity of cardiac lipoprotein lipase is due to Ca
rroll et al., Lipids, 27, pp. 305-307 (1992) and Chuan
g et al., J. Mol. Cell Cardiol., 22,1009-1016 (1990).

Glucosidase inhibitors inhibit the enzymatic hydrolysis of glycoconjugates by glycoside hydrolases, eg, amylase or maltase, into monosaccharides, eg, glucose, that are available in vivo. The rapid metabolism of glucosidases, especially after ingestion of high levels of carbohydrates, causes a state of dietary hyperglycemia, which, in the case of fat or diabetic patients, is associated with increased insulin secretion, increased lipogenesis and lipolysis. Bring about a decrease. After such hyperglycemia, hypoglycemia often occurs because of the increased levels of insulin present. In addition, it is known that both hypoglycemia and chimes, which remain in the stomach, stimulate the production of gastric juice, which initiates or promotes the development of gastritis or duodenal ulcer. Therefore, glucosidase inhibitors are known to be useful in promoting carbohydrate passage through the stomach and in inhibiting intestinal absorption of glucose. Furthermore, the conversion of carbohydrates into adipose tissue lipids and subsequent incorporation of dietary fat into adipose tissue deposition is therefore reduced or delayed with the benefit of reducing or preventing the deleterious abnormalities resulting therefrom.

[0130] Any glucosidase inhibitor can be used in combination with the neurotensin receptor ligand, however, generally preferred glucosidase inhibitors include amylase inhibitors. Amylase inhibitors are glucosidase inhibitors that inhibit the enzymatic degradation of starch or glycogen to maltose. Such inhibition of enzymatic degradation is beneficial in reducing the amount of saccharide available in the body, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.

Various glucosidase and amylase inhibitors are known to those skilled in the art. However,
In the practice of the methods and pharmaceutical compositions of the present invention, generally preferred glucosidase inhibitors are acarbose, adiposine, voglibose, miglitol,
Emiglitate, MDL-25637, Camiglibose, tendamistate, AI-368
8. Trestatin, pradimicin-Q (p
radimicin-Q) and salbostatin.

The glucosidase inhibitor acarbose O-4,6-dideoxy-4-[[(1S, 4R, 5
S, 6S) -4,5,6-trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl] amino] -α-glucopyranosyl- (1 → 4) -O-α-D
-Glucopyranosyl- (1 → 4) -D-glucose, various amino sugar derivatives related thereto, and Actinoplanes strain SE50 (CBS961.7)
0), SE18 (CBS957.70), SE82 (C
BS615.71), SE50 / 13 (614.71)
And their production by microbial culture of SE50 / 110 (674.73) is described in US Pat.
No. 50 and No. 4,174,439, respectively.

The glucosidase inhibitor adiposine consisting of adiposine types 1 and 2 is disclosed in US Pat. No. 4,254,254.
No. 256. Further, methods for the production and purification of adiposin are described in Namiki et al., J. Antibiotics, 35,123.
4-1236 (1982).

The glucosidase inhibitor voglibose 3,4-dideoxy-4-[[2-hydroxy-1-
(Hydroxymethyl) ethyl] amino] -2-C- (hydroxymethyl) -D-epiinositol and various N-substituted pseudoaminosugars related thereto are disclosed in U.S. Pat. No. 4,701,559.

The glucosidase inhibitor miglitol (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4,5-piperidinetriol, and various related compounds 3 , 4,
5-Trihydroxypiperidine is disclosed in U.S. Pat.
No. 9,436.

The glucosidase inhibitor emiglitate p- [2-[(2R, 3R, 4R, 5S) -3,4,4]
Ethyl 5-trihydroxy-2- (hydroxymethyl) piperidino] ethoxy] -benzoate, its various derivatives, and their pharmaceutically acceptable acid addition salts are described in US Pat. No. 5,192,772. It has been disclosed.

Glucosidase inhibitor MDL-25637
2,6-dideoxy-7-O-β-D-glucopyranosyl-2,6-imino-D-glycero-L-glucoheptitol, various homodisaccharides related thereto, and their pharmaceutically acceptable Possible acid addition salts are disclosed in U.S. Patent No. 4,634,765.

The glucosidase inhibitor Camiglibose 6-deoxy-6-[(2R, 3R, 4R, 5S)-
3,4,5-Trihydroxy-2- (hydroxymethyl) piperidino] -α-D-glucopyranoside methyl sesquihydrate and its related deoxynojirimycin (de
Oxy-nojirimycin) derivatives, their various pharmaceutically acceptable salts, and synthetic methods for their preparation are described in US Pat. Nos. 5,157,116 and 5,504,504.
No. 078.

The amylase inhibitor tendamistate, various cyclic peptides related thereto, and methods for their production by microbial culture of Streptomyces tendae strain 4158 or HAG1226 are described in US Pat. No. 4,451,455. It has been disclosed.

The amylase inhibitor AI-3688, various cyclic peptides related thereto, and Streptomyces
Aureofaciens (Streptomyces aureofaciens)
A method for their production by microbial culture of strain FH1656 is disclosed in US Pat. No. 4,623,714.

The amylase inhibitor trestatin consisting of a mixture of trestatin A, trestatin B and trestatin C, various trehalose-containing amino sugars related thereto, and Streptomyces dimorphogenes (Stre
ptomyces dimorphogenes) strain NR-320-OM7H
B and their production by microbial culture of NR-320-OM7HBS are described in US Pat. No. 4,273,765.
Issue.

The glucosidase inhibitor pradimicin-Q,
Actinomadura and Actinomadura
verrucospora) strain R103-3 or A10102
No. 5,091,418 and US Pat. No. 5,217,877, respectively.

The glucosidase inhibitor salbostatin, its various pseudosaccharides, their pharmaceutically acceptable salts, and methods for their production by microbial culture of Streptomyces albus strain ATCC 21838 are described in US Pat. Patent No. 5,
No. 091,524.

Preferred lipase inhibitors are lipstatin, tetrahydrolipstatin, FL-386, WAY
-121898, Bay-n-3176, valilactone, estelacin, ebelactone A, ebelactone B,
RHC80267, including stereoisomers thereof, and compounds selected from the group consisting of the compounds and pharmaceutically acceptable salts of the stereoisomers. Tetrahydrolipstatin compounds are particularly preferred.

Preferred glucosidase inhibitors are acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose,
Including a compound selected from the group consisting of pradimicin-Q and salbostatin. Particularly preferred glucosidase inhibitors further include an amylase inhibitor selected from the group consisting of tendamistate, AI-3688 and trestatin.

The invention further includes the use of a neurotensin receptor ligand in combination with an apo B secretion / MTP inhibitor. Various apo B secretion / MTP inhibitors are known to those skilled in the art. Both apo B secretion / MTP inhibitors
While generally preferred apoB secretion / MTP inhibitors that can be used in the practice of the methods and pharmaceutical compositions of the present invention include, for example, European Patent Application Publication No. EP643057.
No., EP719763, EP735517, EP7
No. 64647, EP7655878, EP779276
No., EP779279, EP799828, EP7
99829, EP802186, EP802188
No., EP802192 and EP802197; P
CT application publication WO96 / 13499, WO96 / 33
No. 193, WO96 / 40640, WO97 / 262
No. 40, WO97 / 43255, WO97 / 4325
7, WO98 / 16526 and WO98 / 235
No. 93; and U.S. Patent Nos. 5,595,872; 5,646,162; 5,684,014; 5,712,279; 5,739,135 and No. 5,789,197.

Particularly preferred apo B secretion / MTP inhibitors are described in PCT Application Publication No. WO 96/40640 and WO 96/40640.
No. 98/23593, which is a biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-ylamide derivative. A particularly preferred apo B secretion / MTP inhibitor disclosed in PCT Application Publication Nos. WO 96/40640 and WO 98/23593 and useful in the methods and pharmaceutical compositions of the present invention is 4'-trifluoromethylbiphenyl-2-carboxylic acid. Acid- [2- (1H- [1,
2,4] triazol-3-ylmethyl) -1,2,2
3,4-tetrahydroisoquinolin-6-yl] -amide and 4'-trifluoromethylbiphenyl-2-carboxylic acid- [2- (acetylaminoethyl) -1,2,2
3,4-tetrahydroisoquinolin-6-yl] -amide.

Another particularly preferred type of apoB secretion / MT
P inhibitors are disclosed in U.S. Patent Nos. 5,595,872; 5,721,279; 5,739,135 and 5,789,197.

Nos. 5,595,872; 5,721,279; 5,739,135 and 5,789,197, and the methods and medicaments of the present invention. A particularly preferred apo B secretion / MTP inhibitor useful in the composition is 9- (4- {4- [4'trifluoromethylbiphenyl-2-carbonyl) -amino] -piperidin-1-yl} -butyl-9H. -Fluorene-9-carboxylic acid- (2,2,2-trifluoroethyl) -amide and 9- {4- [4- (2-benzothiazol-2-ylbenzoylamino) -piperidine-
1-yl] -butyl} -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoroethyl) -amide.

Another class of particularly preferred apo B secretion / MTP inhibitors is described in PCT Application Publication WO 98/1652.
No. 6 discloses. PCT application publication WO98 / 16
A particularly preferred apoB secretion / MTP inhibitor disclosed in US Pat. No. 526 and useful in the methods and pharmaceutical compositions of the present invention is [11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl -7- (prop-
2-enyl) -2,3,11,11a-tetrahydro-
6H-pyrazino [1,2b] isoquinoline-1,4-dione and [11a-R] -cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3 , 11,11a-Tetrahydro-6H
-Pyrazino [1,2b] isoquinoline-1,4-dione.

Another particularly preferred class of apo B secretion / MTP inhibitors is disclosed in US Pat. No. 5,684,014. A particularly preferred apo B secretion / MTP inhibitor disclosed in U.S. Patent No. 5,684,014 and useful in some of the methods and pharmaceutical compositions of the present invention is 2-cyclopentyl-2- [4- (2 , 4-Dimethylpyrido [2,3-b] indol-9-ylmethyl) -phenyl] -N- (2-hydroxy-1-phenylethyl) -acetamide.

Still another type of particularly preferred Apo B
Secretion / MTP inhibitors are disclosed in US Pat. No. 5,646,162.
Issue. A particularly preferred apoB secretion / MTP inhibitor disclosed in US Pat. No. 5,646,162 and useful in the methods and pharmaceutical compositions of the present invention is 2
-Cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] -acetamide.

Yet Another ApoB Secretion / MTP That Can Be Used in Combination with Neurotensin Receptor Ligands
Inhibitors are disclosed in U.S. Reserved Patent Application No. 60 / 164,803. Examples of specific preferred apo B secretion / MTP inhibitors disclosed in that application include 7-aminoquinoline-3-carboxylic acid ethyl ester; 7-[(4 ′
-Trifluoromethylbiphenyl-2-carbonyl)-
Amino] -quinoline-3-carboxylic acid ethyl ester;
7-[(4′-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid; 7
-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (dipyridin-2-ylmethyl) -amide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) ) -Amino] -quinoline-3-carboxylic acid (dipyridin-2-ylmethyl) -amidoethanesulfonate; 7-[(4 '
-Trifluoromethylbiphenyl-2-carbonyl)-
Amino] -quinoline-3-carboxylic acid (dipyridine-2
-Ylmethyl) -amidobisethanesulfonate; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amide; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amidoethanesulfonate; (S) -7-[(4'-tri Fluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3
-Carboxylic acid (phenyldipyridin-2-ylmethyl)
-Amide; (S) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-
3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amidoethanesulfonate; (S) -7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amidobisethanesulfonate; (R) -7-[(4'- (Trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amide; (R) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) ) -Amino] -quinoline-3-carboxylic acid (phenyldipyridin-2-ylmethyl) -amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid Acid (phenyldipyridin-2-ylmethyl) -amidobisethanesulfonate;
7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1
-Carbamoyl-2-phenylethyl) -amide; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (carbamoylphenylmethyl) -amide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino ] -Quinoline-3-carboxylic acid propylamide; 7-
[(4′-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (2,
2,2-trifluoroethyl) -amide; 7-[(4 ′
-Trifluoromethylbiphenyl-2-carbonyl)-
Amino] -quinoline-3-carboxylic acid (1-methyl-1
-Phenylethyl) -amide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]-
Quinoline-3-carboxylic acid cyclopentylamide; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-phenylpropyl) -amide; (R) -7-[(4'-trifluoromethylbiphenyl-2) -Carbonyl) -amino] -quinoline-3-carboxylic acid (1-phenylethyl) -amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-phenylethyl) -amide; 7-[(4′-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-
Carboxylic acid (1-pyridin-2-ylpropyl) -amide; (R) -7-[(4′-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-pyridine- (R) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-pyridin-2-ylpropyl) -amide Ethanesulfonate; (S) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]-
Quinoline-3-carboxylic acid (1-pyridin-2-ylpropyl) -amide; (S) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid ( 1-pyridin-2-ylpropyl) -amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-pyridin-2-
7-ylpropyl) -amidoethanesulfonate;
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (pyridin-2-ylmethyl) -amidoethane sulfonate; 7
-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (2-
7-[(4′-trifluoromethylbiphenyl-2) -pyridin-2-ylethyl) -amidoethanesulfonate
-Carbonyl) -amino] -quinoline-3-carboxylic acid ethylamidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid butylamidoethanesulfonate; 7 -[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (thiophen-2-ylmethyl) -amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2) -Carbonyl) -amino] -quinoline-3
-Carboxylic acid (1-methyl-1-pyridin-2-ylethyl) -amide; (S) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid ( 1-pyridin-2-ylethyl) -amide; (R) -7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid (1-pyridin-2-ylethyl)
-Amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]-
Quinoline-3-carboxylic acid (1-pyridin-2-ylethyl) -amide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3
-Carboxylic acid (1-pyridin-2-ylethyl) -amidoethanesulfonate; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid amide; 7-[(4 '-Trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid benzylamide; 7-[(4'
-Trifluoromethylbiphenyl-2-carbonyl)-
Amino] -quinoline-3-carboxylic acid 4-methoxybenzylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 4-chlorobenzylamide; 7- [ (4′-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 4-methylbenzylamide; 7-[(4′-trifluoromethylbiphenyl-
2-carbonyl) -amino] -quinoline-3-carboxylic acid cyclopropylmethylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]
-Quinoline-3-carboxylic acid 4-fluorobenzylamide; 7-[(4'-trifluoromethylbiphenyl-2
-[Carbonyl] -amino] -quinoline-3-carboxylic acid isopropylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid benzhydrylamide; 7- [ (4 '
-Trifluoromethylbiphenyl-2-carbonyl)-
Amino] -quinoline-3-carboxylic acid cyclopropylamide; 7-[(4'-trifluoromethylbiphenyl-
2-carbonyl) -amino] -quinoline-3-carboxylic acid [1- (4-fluorophenyl) -ethyl] -amide; 7-[(4′-trifluoromethylbiphenyl-2)
-Carbonyl) -amino] -quinoline-3-carboxylic acid 3-methylbenzylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 3-methoxybenzylamide ;
7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 3-
Chlorobenzylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 2-fluorobenzylamide; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 3-fluorobenzylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]- Quinoline-3-carboxylic acid 2-methylbenzylamide; 7-
[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid 2-methoxybenzylamide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino]- Quinoline-3-carboxylic acid 2-chlorobenzylamide; 4'-trifluoromethylbiphenyl-2-carboxylic acid [3-
(Pyrrolidin-1-carbonyl) -quinolin-7-yl] -amide; 4'-trifluoromethylbiphenyl-
2-carboxylic acid [3- (morpholine-4-carbonyl)
-Quinolin-7-yl] -amide; 7-[(4'-trifluoromethylbiphenyl-2-carbonyl) -amino] -quinoline-3-carboxylic acid diethylamide; 4 '
-Trifluoromethylbiphenyl-2-carboxylic acid [3
-(Piperidin-1-carbonyl) -quinolin-7-yl] -amide; and pharmaceutically acceptable salts and prodrugs thereof, and salts of these prodrugs.

Further, the neurotensin receptor ligand can be used in combination with one or more additional compounds that are neurotensin receptor ligands as listed above.

Several abbreviations used in this application are defined below. GTP guanosine 5'-triphosphate GDP guanosine 5'-diphosphate DTT dithiothreitol PEI polyethyleneimine FLIPR fluorescence image plate reader DMSO dimethyl sulfoxide HEPES (N- [2-hydroxyethyl] piperazine-N '-[2-ethane Sulfonic acid]) NT neurotensin BSA bovine serum albumin PBS phosphate buffered saline EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycolbis (β-aminoethylether) N, N, N ′, N′-tetraacetic acid Are all incorporated herein by reference.

The examples provided below illustrate specific embodiments of the present invention in any way, but are not intended to limit the scope of the specification, including the claims, in any way.

[0157]

EXAMPLES Saturation binding: GTPγ [ ³⁵ S] binding Agonist-stimulated GTPγ [ ³⁵ S] binding is a reliable method for measuring agonist potency and titer at G protein-coupled receptors (GPCRs). is there.
GDP binds preferentially to GTP at the inactive heterotrimeric G protein α subunit. When an agonist activates a GPCR, GDP is replaced by GTP (or a GTP analog), causing dissociation of the α subunit from the β and γ subunits of the heterotrimeric G protein. GTPγ [ ³⁵ S] is used in place of GTP to determine agonist potency and titer.

Well stock solution final − + [GTPγ [ ³⁵ S]] [GTPγ [ ³⁵ S]] A 1,2,4 1 nM 0.05 nM B 1,2,3,4 2 nM 0.1 nM C 1,2,3 45 nM 0.25 nM D 1,2,3,4 10 nM 0.5 nM E 1,2,3,4 15 nM 0.75 nM F 1,2,3,4 20 nM 1 nM G 1,2,3,4 100 nM 5 nM H 1,2 , 4 200 nM 10 nM GTPγ [ ³⁵ S] has a specific activity of about 1250 Ci / mmo.
le. GTPγ [ ³⁵ S] has a useful life of about one month. Using a radioactivity calculator well known to those skilled in the art, the effective concentration of stock GTPγ [ ³⁵ S] can be measured.

Add the following to each well in turn: 20 μl binding buffer in “−” wells Neurotensin (1) in binding buffer in “+” wells
20 μl of appropriate concentration of GTPγ [ ³⁵ S] in binding buffer 10 μl
l Membrane 170 from cells expressing neurotensin receptor diluted to 20 μg / 170 μl in binding buffer
μl Binding buffer: 50 mM Hepes / 5 mM MgCl ₂ , pH
7.4 150 mM NaCl 2 μM GDP 1 mM dithiothreitol (DTT) protease inhibitor 100 μg / ml bacitracin 100 μg / ml benzamidine 5 μg / ml aprotinin 5 μg / ml leupeptin protease inhibitor is available from Sigma, St. Louis, MO
Can be obtained from

Washing buffer: 50 mM Hepes / 10 mM MgCl ₂ , pH 7.4
Ice cooling Procedure: The assay is set up in a 96-well filter system (Unifilter® GF / C ^™ , Packard Instrument Company, Meriden, Conn.).

[0161] 2. Incubate for 60-90 minutes with shaking at room temperature. 3. Aspirate the sample into the processing head using a cell collector. Use a presoaked (water good) filter. (Do not use polyethyleneimine (PEI).) Wash 4 times with cold wash buffer.

5. The plate is dried and 25 μl of scintillation fluid is added to each well. 6. Count the sample.

Data analysis: Data are analyzed arbitrarily for radioligand binding saturation curves. Subtract the average of the "minus" wells from the average of the "plus" wells. next,
Convert to pmole / mg (bound protein) and perform a non-linear regression analysis to determine the K _d for GTPγ [ ³⁵ S] binding.

Another measure of CA ⁺⁺ mobilizing agonist potency and titer using the FLIPR assay is the stimulation of intracellular calcium release. Receptors coupled to heterotrimeric G protein Gq result in stimulation of phospholipase C. Activation of phospholipase C may result in the production of diacylglycerol and 1,4,5 inositol triphosphate (IP _3). IP ₃ is then attached to the IP ₃ receptor, stimulates the release of intracellular CA ^++. CA ⁺⁺
The stimulus for release is Fluo-4AM or Fura-2A.
It can be measured using a fluorescent dye that binds CA ⁺⁺ , such as M (Molecular Probes, Inc., Eugene, OR). The following is a protocol for measuring intracellular CA ⁺⁺ release mediated by neurotensin agonists. Measurement of CA ⁺⁺ released by GPCR activation is known to those skilled in the art and other methods can be used.

All the solution components are listed below. 1. Hepes saline and probenecid solutions are prepared fresh for each assay. For small experiments, 1
L assay buffer is sufficient.

2. 11 per 96-well cell plate
Prepare ml dye solution. Separate to 100 μl / well and incubate at 37 ° C. in a CO ₂ incubator for 1 hour.

[0167] 3. Prepare a plate containing the compound to be tested and dilute the compound to be tested in assay buffer (prepare assay buffer immediately before use). Add 100 μl excess of test compound per well. For example, 50
When adding 1 μl of test compound to 100 μl cells, 1
Add 50 μl / well of 3 × concentration of compound.

4. The medium is emptied from the cell plate and washed in a scatron plate washer with assay buffer (if washing large volumes). For smaller plates, it can be carefully aspirated. Equilibrate the cells in assay buffer for 10 minutes.

[0169] 5. Place the cell and drug plates in the FLIPR and perform the experiment. Hepes saline-
1L: 29 ml of 5M NaCl (145 mM final) 5 ml 2M Glucose (10 mM final) 1.65 ml of 3M KCl (5 mM final) 1 ml of 1M MgSO ₄ (1 mM final) 10 ml of 1M Hepes (10 mM final) 2 ml of 1M CaCl ₂ (2 mM final) Probenecid solution-12.5 ml: 925 mg probenecid (2.5 mM final) 1.25 ml 5N NaOH 11.25 ml Hepes saline solution Dye solution (11 ml): Mix 11 ml serum-free medium and 110 μl probenecid solution.

[0170] 2. In a separate tube, add 22 μl of dimethyl sulfoxide (DMSO) to one vial of fluo
Resuspend by pipetting up and down in addition to -4AM. 22 μl of 20% pluronics (pl
uronics) is added to the vial. Mix by pipetting, but pluronics are extremely viscous.
Note: Two fluo-4 vials could be used, but would produce a stronger signal. In this case, the DMSO / Pluronics capacity is doubled.

[0171] 3. Add the fluo-3 / pluronics suspension to the serum-free medium and mix well by inversion. Assay buffer (1% probenecid solution in Hepes saline): 10 ml probenecid solution 1 L Hepes saline saturation binding: [ ¹²⁵ I] nuclear at neurotensin receptor
-Rotensin (NT) The total volume in each well is 200 μl.

The specific activity of [ ¹²⁵ I] NT was 2200 Ci
/ Mmole. The specific activity of the stock solution can be calculated using a radioactivity calculator well known in the art.

Add the following to each well in order: 20 μl of buffer in “−” well 20 μl of 10 μM NT in “+” well 10 μl of appropriate concentration of [ ¹²⁵ I] NT 10 μl 10 μg / 170 μl of membrane diluted to 170 μl Buffer: 50 mM Hepes / 10 mM MgCl ₂ , pH 7.4 0.2% BSA (fraction V) Protease inhibitor 100 μg / ml bacitracin 100 μg / ml benzamidine 5 μg / ml aprotinin 5 μg / ml Leupeptin Washing buffer: 50 mM Hepes / 10 mM MgCl ₂ , pH 7.4,
Ice cooling Procedure: The assay is set up in a 96-well filter system (Unifilter® GF / C ^™ , Packard Instrument Company, Meriden, Conn.).

[0174] 2. 90-120 while shaking at room temperature
Incubate for minutes. 3. Aspirate the sample into the processing head using a cell collector. Use filters presoaked in 0.3% PEI.

4. Wash 4 times with cold wash buffer. 5. The plate is dried and 25 μl of scintillation fluid is added to each well.

6. Count the sample. Data analysis: average “plus” wells to “minus”
Subtract from the well average. Next, fmole / mg (conclusion
And then perform a non-linear regression analysis.
hand,[ ¹²⁵I] K for NT binding_dTo determine.

Note: This procedure can be modified to use tritiated neurotensin. Competitive binding: [ ¹²⁵ I] NT at the neurotensin receptor Up to seven compounds can be examined in a seven-point competition curve in a 96-well format. The first six rows of each compound will be used to double check six compounds at six concentrations. An example for one compound is outlined below. The following compounds are A-
It can be columns 3 and 4 of column F. The seventh compound is
Columns G1 to G12 (-9 to -4).

A1,2-9B1,2-8C1,2-7D1,2-6E1,2-5F1,2-4H1,2 wells were combined with each For total counts (cpm).

H3,4 wells relate to 1 μM NT for measuring non-specific binding. The filter blank (with appropriate buffer, no membrane) is H5,6. The samples are as follows:
It is prepared at a stock solution concentration of 0 ^-3 , 10 ^-4 , 10 ^-5 , 10 ^-6 , 10 ^-7 and 10 ^-8 M. The final concentration will be an order of magnitude less (10 ^-4 to 10 ^-9 ). The stock concentration of the compound is usually 2
Since it is 5 mM, a 25: 1 dilution is required. -4 ~
Prepare 6 tubes labeled -9. 100 μl
Place the binding buffer in each tube. 4 μl
Is added to the tube labeled -4.
Spin and take 11 μl of -4 sample and add to -5 test tube. Repeat until all dilutions have been made.

Add the following to each well in turn: 20 μl of buffer in “total” wells (H1,2). H3, 20 μl of 10 μM NT in 4 wells.

170 μl of buffer solution in H5 and 6 wells. 20 μl of compound at each concentration in appropriate wells. 10 μl of 5 nM [ ¹²⁵ I] NT in all wells.

Membrane 1 diluted to 10 μg / 170 μl
70 μl. Procedure: The assay is set up in a 96-well filter system (Unifilter® GF / C ^™ , Packard Instrument Company, Meriden, Conn.).

2. 90-120 while shaking at room temperature
Incubate for minutes. 3. Aspirate the sample into the processing head using a cell collector. Use a presoaked (0.3% PEI) filter.

4. Wash 4 times with cold wash buffer. 5. The plate is dried and 25 μl of scintillation fluid is added to each well.

6. Count the sample. Binding buffer: 50 mM Hepes / 10 mM MgC
l ₂ , pH 7.4 (made from 10X stock solution) 0.2% BSA (fraction V) Protease inhibitor (prepared as 100X stock solution) 100 μg / ml bacitracin 100 μg / ml benzamidine 5 μg / ml aprotinin 5 μg / ml Leupeptin Washing buffer: 50 mM Hepes / 10 mM MgC
l _2, pH 7.4, ice compound to GTPγ ^[35 S] binding assays maximum seven-mediated agonist (created from 10X stock), be examined at seven points competition curves in the 96-well format it can. The first six rows of each compound will be used to double check six compounds at six concentrations. An example for one compound is outlined below. The following compounds are A-
It can be columns 3 and 4 of column F. The seventh compound is
Columns G1 to G12 (-9 to -4).

A1,2-9B1,2-8C1,2-7D1,2-6E1,2-5F1,2-4H1-4 wells bound the basic GTPγ [ ³⁵ S].

H5,6 wells are for cold 10 μM GTPγS measuring non-specific binding. The filter blank (with appropriate buffer, no membrane) is H7,8.

The samples were as follows: 10 ⁻³ , 10 ⁻⁴ , 10 ⁻⁵ ,
Prepared at stock concentrations of 10 ^-6 , 10 ^-7 , and 10 ^-8 M. The final concentration will be an order of magnitude less (10 ^-4 to 10 ^-9 ). Since the stock concentration of the compound is usually 25 mM, 25:
One dilution is required. Prepare six tubes labeled -4 to -9. 100 μl of binding buffer is placed in each tube. Add 4 μl of the 25 mM stock solution to the tube labeled -4. Spin 11 μl of -4
Take a sample and add to a -5 tube. Repeat until all dilutions have been made. The first sample is always natural neurotensin.

Add the following to each well in turn: H1
-20 μl of buffer in 4 wells. 20 μl of compound at each concentration in appropriate wells.

100 μM GTPγS in H5 and 6 wells
20 μl. GTPγ [ ³⁵ S] at an appropriate concentration
l. 170 μl membrane diluted to 20 μg / 170 μl in binding buffer.

GTPγS binding buffer: (freshly made) 50 mM Hepes / 5 mM MgCl ₂ , pH 7.4 150 mM NaCl (3 M) 2 μM GDP (10 mM) 1 mM DTT (1 M) Protease inhibitor 100 μg / ml bacitracin 100 μg / ml benzamidine 5 μg / ml aprotinin 5 μg / ml leupeptin Washing buffer: 50 mM Hepes / 10 mM MgC
l ₂ , pH 7.4, ice-cooled Procedure: The assay is set up in a 96-well filter system (Unifilter® GF / C ^™ , Packard Instrument Company, Meriden, Conn.).

[0192] 2. Incubate for 60 minutes with shaking at room temperature. 3. Aspirate the sample into the processing head using a cell collector. Use a presoaked (water good) filter. Do not use PEI.

[0193] 4. Wash 4 times with cold wash buffer. 5. The plate is dried and 25 μl of scintillation fluid is added to each well.

1.6. Count the sample. Data analysis: Data are analyzed arbitrarily for dose response curves. Convert to bound pmoles / mg.

Membrane preparation from cells Harvest cells. For adherent cells (usually
10 Prepare 150 mm plate), PBS / ED
Cells are removed using TA. 1000X at 4 ° C
Spin at g for 10 minutes. The supernatant is removed and resuspended in 10 ml of homogenization buffer. Leave on ice for 10 minutes. It is noted that cells such as HEK293 cells or CHO cells expressing recombinant neurotensin receptor can be used. In addition, natural neurotensin receptors such as HT29 cells or SW cells can be used.

[0196] 3. Homogenize using a tight fit glass / glass dounce homogenizer with 20 strokes. 4. Nuclei and unlysed cells are centrifuged off by centrifuging the sample at 1000 × g for 10 minutes at 4 ° C.

[0197] 5. Transfer the supernatant to a new tube. 6. 4 ℃ in Sorvall SS34 (or similar)
And centrifugation at 25,000 Xg for 20 minutes twice.

7. Resuspend in an appropriate volume of homogenization buffer, which is 1-5 mg / m
would result in a protein concentration of 1. A 250 μl aliquot of each sample is made by adding one 10 μl aliquot for protein measurement. For protein assays,
Dilute 1: 5 and measure.

10x buffer for homogenization: 10mM EDTA 10mM EGTA 10mM Na bicarbonate pH 7.4 100x protease inhibitor: 10mg / ml benzamidine 10mg / ml bacitracin 0.5mg / ml leupeptin 0.5mg / ml aprotinin

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/04 A61P 3/10 3/06 9/10 3/10 15/10 9/10 43/00 121 15/10 A61K 37/02 43/00 121 37/24 F term (reference) 4C084 AA17 AA20 BA03 BA44 DC50 MA02 ZA45 ZA70 ZA81 ZC33 ZC35 4C086 AA01 DA09 MA02 MA04 NA05 ZA45 ZA70 ZA81 ZC33 ZC35 ZC75

Claims (16)

[Claims] 1. A pharmaceutical composition for treating obesity, comprising a compound that is therapeutically effective in obese patients or at risk of becoming obese, and that is a neurotensin receptor ligand. 2. The pharmaceutical composition according to claim 1, wherein the neurotensin receptor ligand is a neurotensin-1 receptor ligand. 3. The pharmaceutical composition according to claim 1, wherein the neurotensin receptor ligand is a neurotensin-2 receptor ligand. 4. The pharmaceutical composition according to claim 1, wherein the neurotensin receptor ligand is a neurotensin-3 receptor ligand. 5. The pharmaceutical composition according to claim 1, wherein the ligand is an agonist. 6. The pharmaceutical composition according to claim 1, wherein the ligand is an antagonist. 7. The pharmaceutical composition according to claim 1, wherein the neurotensin receptor ligand is a neurotensin-1 receptor agonist. 8. A therapeutically effective, selective neurotensin for obese patients or patients at risk of becoming obese.
A pharmaceutical composition for treating obesity, comprising a compound that is a 1 receptor agonist. 9. A pharmaceutical composition comprising: (a) a compound that is a neurotensin receptor ligand;
And (b) the above pharmaceutical composition comprising a second compound useful for treating obesity, diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia. . 10. The pharmaceutical composition according to claim 9, wherein the neurotensin receptor ligand is a neurotensin-1 receptor agonist. 11. The method of claim 11, wherein the second compound is a β ₃ adrenergic receptor agonist, a cholecystokinin A agonist,
Monoamine reuptake inhibitors, sympathomimetics, serotonin agonists, dopamine agonists, melanocyte stimulating hormone receptor agonists or mimetics, melanocyte stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin, Leptin analog, leptin receptor agonist, galanin antagonist, bombesin agonist, neuropeptide Y antagonist, thyroid analog, dehydroepiandrosterone or its analog, glucocorticoid receptor agonist or antagonist, orexin receptor antagonist, urocortin binding protein antagonist The pharmaceutical composition according to claim 9, which is a glucagon-like peptide-1 receptor agonist or a ciliary neurotrophic factor. 12. A kit, comprising: (a) a first pharmaceutical composition comprising a compound that is a neurotensin receptor ligand; (b) obesity, diabetes, sexual dysfunction, atherosclerosis, insulin resistance A second pharmaceutical composition comprising a compound useful for the treatment of impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia; and (c) the kit comprising a container for the first and second compositions. 13. The neurotensin receptor ligand is a neurotensin-1 receptor agonist.
The kit according to 1. 14. The second pharmaceutical composition may be a β ₃ adrenergic receptor agonist, a cholecystokinin A agonist, a monoamine reuptake inhibitor, a sympathomimetic, a serotonin agonist, a dopamine agonist, a melanocyte stimulating hormone receptor. Body agonists or mimetics, melanocyte stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin, leptin analogs, leptin receptor agonists, galanin antagonists, bombesin agonists, neuropeptide Y antagonists, thyroid analogs , Dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, Exaggeration like peptide-1 receptor agonist or a kit of claim 12 which is ciliary neurotrophic factor. 15. A neurotherapeutically effective patient with diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia or a patient at risk thereof. A pharmaceutical composition comprising a tensin receptor ligand for treating diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertriglyceridemia. 16. The pharmaceutical composition according to claim 15, wherein the neurotensin receptor ligand is a neurotensin-1 receptor ligand.